Jump to content

Heritability of autism

From Wikipedia, the free encyclopedia

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.[1][2]

Autism is known to have a strong genetic component, with studies consistently demonstrating a higher prevalence among siblings and in families with a history of autism. This led researchers to investigate the extent to which genetics contribute to the development of autism. Numerous studies, including twin studies and family studies, have estimated the heritability of autism to be around 80 to 90%,[3] indicating that genetic factors play a substantial role in its etiology. Heritability estimates do not imply that autism is solely determined by genetics, as environmental factors also contribute to the development of the disorder.[4]

Studies of twins from 1977 to 1995 estimated the heritability of autism to be more than 90%; in other words, that 90% of the differences between autistic and non-autistic individuals are due to genetic effects.[5] When only one identical twin is autistic, the other often has learning or social disabilities.[6] For adult siblings, the likelihood of having one or more features of the broad autism phenotype might be as high as 30%,[7] much higher than the likelihood in controls.[8]

A variety of genetic associations with autism spectrum disorder have been reported. This Manhattan plot shows the statistical significance (but not necessarily the strength) of each variant in a scan across the entire genome. The plot is similar to those in published articles. [9][10]

Though genetic linkage analysis have been inconclusive,[11] many association analyses have discovered genetic variants associated with autism.[12] For each autistic individual, mutations in many genes are typically implicated. Mutations in different sets of genes may be involved in different autistic individuals. There may be significant interactions among mutations in several genes, or between the environment and mutated genes. By identifying genetic markers inherited with autism in family studies, numerous candidate genes have been located, most of which encode proteins involved in neural development and function.[13][14] However, for most of the candidate genes, the actual mutations that increase the likelihood for autism have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to single chromosome abnormalities such as fragile X syndrome or 22q13 deletion syndrome.[15][16]

10–15% of autism cases may result from single gene disorders or copy number variations (CNVs)—spontaneous alterations in the genetic material during meiosis that delete or duplicate genetic material.[17][18][19] These sometimes result in syndromic autism, as opposed to the more common idiopathic autism.[20][21] Sporadic (non-inherited) cases have been examined to identify candidate genetic loci involved in autism. A substantial fraction of autism may be highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.[22]

Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array comparative genomic hybridization (CGH) improves,[22] several results in this area have been described incautiously, possibly misleading the public into thinking that a large proportion of autism is caused by CNVs and is detectable via array CGH, or that detecting CNVs is tantamount to a genetic diagnosis.[23] The Autism Genome Project database contains genetic linkage and CNV data that connect autism to genetic loci and suggest that every human chromosome may be involved.[24] It may be that using autism-related sub-phenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci.[25]

Twin studies

[edit]

Twin studies provide a unique opportunity to explore the genetic and environmental influences on autism spectrum disorder (ASD). By studying identical twins, who share identical DNA, and fraternal twins, who share about half of their DNA, researchers can estimate the heritability of autism by comparing the rates of when one twin is diagnosed with autism while the other is not in identical vs. fraternal twins. Twin studies are a helpful tool in determining the heritability of disorders and human traits in general. They involve determining concordance of characteristics between identical (monozygotic or MZ) twins and between fraternal (dizygotic or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins.

A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and assortative mating.

An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.[26] An example of a human characteristics that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.[27]

Identical twin studies put autism's heritability in a range between 36% and 95.7%, with concordance for a broader phenotype usually found at the higher end of the range.[28] Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population.

Notable twin studies have attempted to shed light on the heritability of autism.

A small-scale study in 1977 was the first of its kind to look into the heritability of autism. It involved 10 DZ twins and 11 MZ twins in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of "cognitive abnormalities" was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.[29]

A 1979 case report discussed a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had had infrequent seizures, remained autistic. The report noted that genetic factors were not "all-important" in the development of twins.[30]

In 1985, a study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.[31]

In a 1989 study, Nordic countries were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for "cognitive disorder" were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.[32]

A British twin sample was reexamined in 1995 and a 60% concordance was found for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that "obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors."[33]

A 1999 study looked at social cognitive skills in the general-population of children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.[34]

In 2000, a study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.[35]

A 2004 study looked at 16 MZ twins and found a concordance of 43.75% for "strictly defined autism". Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.[36]

Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotic twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that "the levels of clinical features seen in autism may be a result of mainly independent genetic traits."[37]

An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.[38]

One critic of the pre-2006 twin studies said that they were too small and their results can be plausibly explained on non-genetic grounds.[39]

Sibling studies

[edit]

A study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a "lesser variant" of autism.[8]

A study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, "showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks."[40]

A 2005 Danish study looked at "data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity." It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with Asperger syndrome or PDD was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that "the risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age."[41]

A study in 2007 looked at a database containing pedigrees of 86 families with two or more autistic children and found that 42 of the third-born male children showed autistic symptoms, suggesting that parents had a 50% chance of passing on a mutation to their offspring. The mathematical models suggest that about 50% of autistic cases are caused by spontaneous mutations. The simplest model was to divide parents into two risk classes depending on whether the parent carries a pre-existing mutation that causes autism; it suggested that about a quarter of autistic children have inherited a copy number variation from their parents.[42]

Other family studies

[edit]

A 1994 study looked at the personalities of parents of autistic children, using parents of children with Down syndrome as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive" compared to parents whose children did not have autism.[43]

A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.[44]

Autism was found to occur more often in families of physicists, engineers and scientists. 12.5% of the fathers and 21.2% of the grandfathers (both paternal and maternal) of children with autism were engineers, compared to 5% of the fathers and 2.5% of the grandfathers of children with other syndromes.[45] Other studies have yielded similar results.[46][47] Findings of this nature have led to the coinage of the term "geek syndrome".[48]

A 2001 study of brothers and parents of autistic boys looked into the phenotype in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a "cognitive style" (weak central coherence) that can confer information-processing advantages.[49]

A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.[50] Another 2005 study focused on sub-threshold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.[51]

A 2005 report examined the family psychiatric history of 58 subjects with Asperger syndrome (AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.[52] According to a 2022 study held on 86 mother-child dyads across 18 months, "prior maternal depression didn’t predict child behavior problems later."[53]

Twinning risk

[edit]

It has been suggested that the twinning process itself is a risk factor in the development of autism, presumably due to perinatal factors.[54] However, three large-scale epidemiological studies have refuted this idea.[5][55] These studies took place in California, Sweden, and Australia.[55] One study done in Western Australia, utilized the Maternal and Child Health Research Database that houses birth records for all infants born, including infants and later children diagnosed with autism spectrum disorder. During this study, the population analyzed for the incidence of Autism Spectrum Disorder was restricted to those children with birth years between 1980 and 1995. The focus was on the incidence of autism spectrum disorder in the twin population in comparison to the non twin population. The following two studies,[33][55] explored the risk of Autism spectrum disorder in the twin population. The conclusion that the twinning process alone is not a risk factor was drawn.[55] In these studies the data exemplified that both MZ twins will have autism spectrum disorder, but only one of the DZ twins will have autism spectrum disorder with an incidence rate of 90% in MZ twins compared to 0% in DZ twins.[33] The high symmetry in MZ twins can explain the high symmetry of autism spectrum disorder in MZ twins outcome compared to DZ twins and non twin siblings.[55]

Proposed models

[edit]
See also: Missing heritability problem

Twin and family studies show that autism is a highly heritable condition, but they have left many questions for researchers, most notably:

  • Why is fraternal twin concordance so low considering that identical twin concordance is high?
  • Why are parents of autistic children typically non-autistic?
  • Which factors could be involved in the failure to find a 100% concordance in identical twins?
  • Is profound intellectual disability a characteristic of the genotype or something totally independent?

Clues to the first two questions come from studies that have shown that at least 30% of individuals with autism have spontaneous de novo mutations that occurred in the father's sperm or mother's egg that disrupt important genes for brain development. These spontaneous mutations are likely to cause autism in families where there is no family history of the disorder.[56]

The concordance between identical twins is not quite 100% for two reasons, because these mutations have variable 'expressivity' and their effects manifest differently due to chance effects, epigenetic, and environmental factors. Also spontaneous mutations can potentially occur specifically in one embryo and not the other after conception.[57] The likelihood of developing intellectual disability is dependent on the importance of the gene to brain development and how the mutation changes this function, also playing a role is the genetic and environmental background upon which a mutation occurs.[58] The recurrence of the same mutations in multiple individuals affected by autism has led Brandler and Sebat to suggest that the spectrum of autism is breaking up into quanta of many different genetic disorders.[58]

Single genes

[edit]

The most parsimonious explanation for cases of autism where a single child is affected and there is no family history or affected siblings is that a single spontaneous mutation that impacts one or multiple genes is a significant contributing factor.[58][59] Tens of individual genes or mutations have been definitively identified and are cataloged by the Simons Foundation Autism Research Initiative.[60][61]

Examples of autism that has arisen from a rare or de novo mutation in a single-gene or locus include neurodevelopmental disorders like fragile X syndrome; metabolic conditions (for example, propionic acidemia);[62] and chromosomal disorders like 22q13 deletion syndrome and 16p11.2 deletion syndrome.[63]

Deletion (1), duplication (2) and inversion (3) are all chromosome abnormalities that have been implicated in autism.[22]

These mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. For example, carriers of the 16p11.2 deletion have a mean IQ 32 points lower than their first-degree relatives that do not carry the deletion, however only 20% are below the threshold IQ of 70 for intellectual disability, and only 20% have autism.[64][65] Around 85% have a neurobehavioral diagnosis, including autism, ADHD, anxiety disorders, mood disorders, gross motor delay, and epilepsy, while 15% have no diagnosis.[65] Alongside these neurobehavioral phenotypes, the 16p11.2 deletions / duplications have been associated with macrocephaly / microcephaly, body weight regulation, and the duplication in particular is associated with schizophrenia.[64][66][67] Controls that carry mutations associated with autism or schizophrenia typically present with intermediate cognitive phenotypes or fecundity compared to neurodevelopmental cases and population controls.[68] Therefore, a single mutation can have multiple different effects depending on other genetic and environmental factors.

Multigene interactions

[edit]

In this model, autism often arises from a combination of common, functional variants of genes. Each gene contributes a relatively small effect in increasing the risk of autism. In this model, no single gene directly regulates any core symptom of autism such as social behavior. Instead, each gene encodes a protein that disrupts a cellular process, and the combination of these disruptions, possibly together with environmental influences,[69] affect key developmental processes such as synapse formation. For example, one model is that many mutations affect MET and other receptor tyrosine kinases, which in turn converge on disruption of ERK and PI3K signaling.[63]

Two family types

[edit]

In this model most families fall into two types: in the majority, sons have a low risk of autism, but in a small minority their risk is near 50%. In the low-risk families, sporadic autism is mainly caused by spontaneous mutation with poor penetrance in daughters and high penetrance in sons. The high-risk families come from (mostly female) children who carry a new causative mutation but are unaffected and transmit the dominant mutation to grandchildren.[42]

Epigenetic

[edit]
Main article: Epigenetics of autism

Several epigenetic models of autism have been proposed.[70] These are suggested by the occurrence of autism in individuals with fragile X syndrome, which arises from epigenetic mutations, and with Rett syndrome, which involves epigenetic regulation factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.[71]

Genomic imprinting

[edit]

Genomic imprinting models have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD.[72] One hypothesis is that autism is in some sense diametrically opposite to schizophrenia and other psychotic-spectrum conditions, that alterations of genomic imprinting help to mediate the development of these two sets of conditions, and that ASD involves increased effects of paternally expressed genes, which regulate overgrowth in the brain, whereas schizophrenia involves maternally expressed genes and undergrowth.[73]

Environmental interactions

[edit]

Though autism's genetic factors explain most of autism risk, they do not explain all of it. A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult.[74] Several theories based on environmental factors have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects; others focus on the environment after birth, such as children's diets. All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, strong evidence that autism arises very early in development.[75] Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies,[76] extensive searches are underway.[77]

Sex bias

[edit]

Autism spectrum disorder affects all races, ethnicities, and socioeconomic groups. Still, more males than females are affected across all cultures,[78] the ratios of males-to-females is appropriately 3 to 1.[79] A study analyzed the Autism Genetics Resource Exchange (AGRE database), which holds resources, research, and records of autism spectrum disorder diagnosis. In this study, it was concluded that when a spontaneous mutation causes autism spectrum disorder (ASD), there is high penetrance in males and low penetrance in females.[79][80] A study published in 2020 explored the reason behind this idea further.[81] It is commonly known that the main difference between males and females is the fact that males have one X and one Y sex chromosome whereas female have two X chromosomes. This leads to the idea that there is a gene on the X chromosome that is not on the Y that is involved with the sex bias of ASD.[81][78]

In another study, it has been found that the gene called NLGN4, when mutated, can cause ASD.[82] This gene and other NLGN genes are important for neuron communications.[78] This NLGN4 gene is found on both the X (NLGN4X) and the Y (NLGN4Y) chromosome. The sex chromosomes are 97% identical.[78][81] It has been determined that most of the mutations that occur are located on the NLGN4X gene.[78][82] Research into the differences between NLGN4X and NLGN4Y found that the NLGN4Y protein has poor surface expectations and poor synapses regulations, leading to poor neuron communication.[78][81] Researchers concluded that males have a higher incidence of autism when the mechanism is NLGN4X-associated.[78] This association was concluded since females have two X chromosomes; if there is a mutation in a gene on an X chromosome, the other X chromosome can be used to compensate for the mutation. Whereas males have only one X chromosome, meaning that if there is a mutation in a gene on an X chromosome, then that is the only copy of the gene and it will be used. The genomic difference between males and females is one mechanism that leads to the higher incidence of ASD in males.[78][81][82]

Candidate gene loci

[edit]

Known genetic syndromes, mutations, and metabolic diseases account for up to 20% of autism cases.[83] A number of alleles have been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypes that are manifested as the autism phenotype. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele combinations involved in the etiology of autism.

A 2008 study compared genes linked with autism to those of other neurological diseases, and found that more than half of known autism genes are implicated in other disorders, suggesting that the other disorders may share molecular mechanisms with autism.[84]

Primary

[edit]
Gene OMIM/# Locus Description
CDH9, CDH10 5p14.1 A 2009 pair of genome-wide association studies found an association between autism and six single-nucleotide polymorphisms in an intergenic region between CDH10 (cadherin 10) and CDH9 (cadherin 9). These genes encode neuronal cell-adhesion molecules, implicating these molecules in the mechanism of autism.[85]
CDH8 16q21 A family based study identified a deletion of CDH8 that was transmitted to three out of three affected children and zero out of four unaffected siblings.[86] Further evidence for the role of CDH8 comes from a spontaneous 1.52 megabase inversion that disrupts the gene in an affected child.[87]
MAPK3 16p11.2 A 2008 study observed a de novo deletion of 593 kb on this chromosome in about 1% of persons with autism, and similarly for the reciprocal duplication of the region.[88] Another 2008 study also found duplications and deletions associated with ASD at this locus.[89] This gene encodes ERK1, one of the extracellular signal regulated kinase subfamily of mitogen-activated protein kinases which are central elements of an intracellular signaling pathways that transmits signals from cell surfaces to interiors. 1% of autistic children have been found to have either a loss or duplication in a region of chromosome 16 that encompasses the gene for ERK1. A similar disturbance in this pathway is also found in neuro-cardio-facial-cutaneous syndromes (NCFC), which are characterized by cranio-facial development disturbances that also can be found in some cases of autism.[90]
SERT (SLC6A4) 17q11.2 This gene locus has been associated with rigid-compulsive behaviors. Notably, it has also been associated with depression but only as a result of social adversity, although other studies have found no link.[91] Significant linkage in families with only affected males has been shown.[92][93] Researchers have also suggested that the gene contributes to hyperserotonemia.[94] However, a 2008 meta-analysis of family- and population-based studies found no significant overall association between autism and either the promoter insertion/deletion (5-HTTLPR) or the intron 2 VNTR (STin2 VNTR) polymorphisms.[95]
CACNA1G 17q21.33 Markers within an interval containing this gene are associated with ASD at a locally significant level. The region likely harbors a combination of multiple rare and common alleles that contribute to genetic risk for ASD.[96]
GABRB3, GABRA4 multiple GABA is the primary inhibitory neurotransmitter of the human brain. Ma et al. (2005) concluded that GABRA4 is involved in the etiology of autism, and that it potentially increases autism risk through interaction with GABRB1.[97] The GABRB3 gene has been associated with savant skills.[98] The GABRB3 gene deficient mouse has been proposed as a model of ASD.[99]
EN2 7q36.2 Engrailed 2 is believed to be associated with cerebellar development. Benayed et al.. (2005) estimate that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population.[100] But at least one study has found no association.[101]
? 3q25-27 A number of studies have shown a significant linkage of autism and Asperger syndrome with this locus.[102][103] The most prominent markers are in the vicinity of D3S3715 and D3S3037.[104]
RELN 7q21-q36 In adults, Reelin glycoprotein is believed to be involved in memory formation, neurotransmission, and synaptic plasticity. A number of studies have shown an association between the REELIN gene and autism,[105][106] but a couple of studies were unable to duplicate linkage findings.[107]
SLC25A12 2q31 This gene encodes the mitochondrial aspartate/glutamate carrier (AGC1). It has been found to have a significant linkage to autism in some studies,[108][109][110] but linkage was not replicated in others,[111] and a 2007 study found no compelling evidence of an association of any mitochondrial haplogroup in autism.[112]
HOXA1 and HOXB1 multiple A link has been found between HOX genes and the development of the embryonic brain stem. In particular, two genes, HOXA1 and HOXB1, in transgenic 'knockout' mice, engineered so that these genes were absent from the genomes of the mice in question, exhibited very specific brain stem developmental differences from the norm, which were directly comparable to the brain stem differences discovered in a human brain stem originating from a diagnosed autistic patient.[113]

Conciatori et al.. (2004) found an association of HOXA1 with increased head circumference.[114] A number of studies have found no association with autism.[115][116][117] The possibility remains that single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions. Tischfield et al.. published a paper which suggests that because HOXA1 is implicated in a wide range of developmental mechanisms, a model involving multiple allelic variants of HOXA1 in particular may provide useful insights into the heritability mechanisms involved.[118] Additionally, Ingram et al.. alighted upon additional possibilities in this arena.[119] Transgenic mouse studies indicate that there is redundancy spread across HOX genes that complicate the issue, and that complex interactions between these genes could play a role in determining whether or not a person inheriting the requisite combinations manifests an autistic spectrum condition[120]—transgenic mice with mutations in both HOXA1 and HOXB1 exhibit far more profound developmental anomalies than those in which only one of the genes differs from the conserved 'norm'.

In Rodier's original work, teratogens are considered to play a part in addition, and that the possibility remains open for a range of teratogens to interact with the mechanisms controlled by these genes unfavourably (this has already been demonstrated using valproic acid, a known teratogen, in the mouse model).[121]

PRKCB1 16p11.2 Philippi et al. (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated.[122]
TAOK2 16p11.2 Richter et al. (2018) found a strong association between this gene and autism.[123]
MECP2 300496, AUTSX3 Xq28 Mutations in this gene can give rise to autism spectrum disorders and related postnatal neurodevelopmental disorders.[124]
UBE3A 15q11.2–q13 The maternally expressed imprinted gene UBE3A has been associated with Angelman syndrome. MeCP2 deficiency results in reduced expression of UBE3A in some studies.[125]
SHANK3 (ProSAP2) 22q13 The gene called SHANK3 (also designated ProSAP2) regulates the structural organization of neurotransmitter receptors in post-synaptic dendritic spines making it a key element in chemical binding crucial to nerve cell communication.[126] SHANK3 is also a binding partner of chromosome 22q13 (i.e. a specific section of Chromosome 22) and neuroligin proteins; deletions and mutations of SHANK3, 22q13 (i.e. a specific section of Chromosome 22) and genes encoding neuroligins have been found in some people with autism spectrum disorders.[127]

Mutations in the SHANK3 gene have been strongly associated with the autism spectrum disorders. If the SHANK3 gene is not adequately passed to a child from the parent (haploinsufficiency) there will possibly be significant neurological changes that are associated with yet another gene, 22q13, which interacts with SHANK3. Alteration or deletion of either will effect changes in the other.[127]

A deletion of a single copy of a gene on chromosome 22q13 has been correlated with global developmental delay, severely delayed speech or social communication disorders and moderate to profound delay of cognitive abilities. Behavior is described as "autistic-like" and includes high tolerance to pain and habitual chewing or mouthing[127] (see also 22q13 deletion syndrome). This appears to be connected to the fact that signal transmission between nerve cells is altered with the absence of 22q13.

SHANK3 proteins also interact with neuroligins at the synapses of the brain further complicating the widespread effects of changes at the genetic level and beyond.[128]

NLGN3 300425, AUTSX1 Xq13 Neuroligin is a cell surface protein (homologous to acetylcholinesterase and other esterases) that binds to synaptic membranes.[129] Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory);[130] In this way, neuroligins help to ensure signal transitions between nerve cells. Neuroligins also regulate the maturation of synapses and ensure there are sufficient receptor proteins on the synaptic membrane.

Mice with a neuroligin-3 mutation exhibit poor social skills but increased intelligence.[131] Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders.[128] However, a 2008 study found no evidence for involvement of neuroligin-3 and neuroligin-4x with high-functioning ASD.[132]

MET 7q31 The MET gene (MET receptor tyrosine kinase gene) linked to brain development, regulation of the immune system, and repair of the gastrointestinal system, has been linked to autism. This MET gene codes for a protein that relays signals that turn on a cell's internal machinery. Impairing the receptor's signaling interferes with neuron migration and disrupts neuronal growth in the cerebral cortex and similarly shrinks the cerebellum—abnormalities also seen in autism.[133]

It is also known to play a key role in both normal and abnormal development, such as cancer metastases. A mutation of the gene, rendering it less active, has been found to be common amongst children with autism.[133] Mutation in the MET gene demonstrably raises risk of autism by 2.27 times.[134]

NRXN1 2q32 In February 2007, researchers in the Autism Genome Project (an international research team composed of 137 scientists in 50 institutions) reported possible implications in aberrations of a brain-development gene called neurexin 1 as a cause of some cases of autism.[24] Linkage analysis was performed on DNA from 1,181 families in what was the largest-scale genome scan conducted in autism research at the time.

The objective of the study was to locate specific brain cells involved in autism to find regions in the genome linked to autism susceptibility genes. The focus of the research was copy number variations (CNVs), extra or missing parts of genes. Each person does not actually have just an exact copy of genes from each parent. Each person also has occasional multiple copies of one or more genes or some genes are missing altogether. The research team attempted to locate CNVs when they scanned the DNA.

Neurexin 1 is one of the genes that may be involved in communication between nerve cells (neurons). Neurexin 1 and other genes like it are very important in determining how the brain is connected from cell to cell, and in the chemical transmission of information between nerve cells. These genes are particularly active very early in brain development, either in utero or in the first months or couple of years of life. In some families their autistic child had only one copy of the neurexin 1 gene.

Besides locating another possible genetic influence (the findings were statistically insignificant), the research also reinforced the theory that autism involves many forms of genetic variations.

A 2008 study implicated the neurexin 1 gene in two independent subjects with ASD, and suggested that subtle changes to the gene might contribute to susceptibility to ASD.[135]

A Neurexin 1 deletion has been observed occurring spontaneously in an unaffected mother and was passed on to an affected child, suggesting that the mutation has incomplete penetrance.[87]

CNTNAP2 7q35-q36 Multiple 2008 studies have identified a series of functional variants in the CNTNAP2 gene, a member of the neurexin superfamily, that implicate it as contributing to autism.[69][136][137][138]
FOXP2 7q31 The FOXP2 gene is of interest because it is known to be associated with developmental language and speech deficits.[139][140] A 2008 study found that FOXP2 binds to and down-regulates CNTNAP2, and that the FOXP2-CNTNAP2 pathway links distinct syndromes involving disrupted language.[141]
GSTP1 11q13 A 2007 study suggested that the GSTP1*A haplotype of the glutathione S-transferase P1 gene (GSTP1) acts in the mother during pregnancy and increases the likelihood of autism in the child.[142]
PRL, PRLR, OXTR multiple A 2014 meta-analysis found significant associations between autism and several single-nucleotide polymorphisms in the OXTR gene.[143]

Others

[edit]

There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes.[144][145][146]

A few examples of loci that have been studied are the 17q21 region,[147][148] the 3p24-26 locus,[144] PTEN,[149] 15q11.2–q13[125] and deletion in the 22q11.2 area.[150]

Homozygosity mapping in pedigrees with shared ancestry and autism incidence has recently implicated the following candidate genes: PCDH10, DIA1 (formerly known as C3ORF58), NHE9, CNTN3, SCN7A, and RNF8. Several of these genes appeared to be targets of MEF2,[151][152] one of the transcription factors known to be regulated by neuronal activity[153] and that itself has also recently been implicated as an autism-related disorder candidate gene.[154]

References

[edit]
  1. ^ Abrahams BS, Geschwind DH (May 2008). "Advances in autism genetics: on the threshold of a new neurobiology". Nature Reviews. Genetics. 9 (5): 341–355. doi:10.1038/nrg2346. PMC 2756414. PMID 18414403.
  2. ^ Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA, Grove J, et al. (July 2017). "Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders". Nature Genetics. 49 (7): 978–985. doi:10.1038/ng.3863. PMC 5552240. PMID 28504703. Common polygenic variation, distributed across the genome, accounts for at least 20% of ASD liability. De novo single-nucleotide and copy number variants can have a strong effect on the individuals who carry them but account for less liability at a population level (<10%).
  3. ^ Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A (September 2017). "The Heritability of Autism Spectrum Disorder". JAMA. 318 (12): 1182–1184. doi:10.1001/jama.2017.12141. PMC 5818813. PMID 28973605.
  4. ^ Buxbaum JD, Hof PR (25 October 2012). The Neuroscience of Autism Spectrum Disorders. Academic Press. ISBN 9780123919243. Retrieved 2023-07-02.
  5. ^ a b Freitag CM (January 2007). "The genetics of autistic disorders and its clinical relevance: a review of the literature". Molecular Psychiatry. 12 (1): 2–22. doi:10.1038/sj.mp.4001896. PMID 17033636. S2CID 205678822.
  6. ^ Le Couteur A, Bailey A, Goode S, Pickles A, Robertson S, Gottesman I, Rutter M (October 1996). "A broader phenotype of autism: the clinical spectrum in twins". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 37 (7): 785–801. doi:10.1111/j.1469-7610.1996.tb01475.x. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 8923222.
  7. ^ Folstein SE, Rosen-Sheidley B (December 2001). "Genetics of autism: complex aetiology for a heterogeneous disorder". Nature Reviews. Genetics. 2 (12): 943–55. doi:10.1038/35103559. PMID 11733747. S2CID 9331084.
  8. ^ a b Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M, et al. (July 1994). "A case-control family history study of autism". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 35 (5): 877–900. doi:10.1111/j.1469-7610.1994.tb02300.x. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 7962246.
  9. ^ Jiang, Rui; Huang, Wentao; Qiu, Xinqi; Chen, Jianyi; Luo, Ruibang; Zeng, Ruijie; Tong, Shuangshuang; Lyu, Yanlin; Sun, Panpan; Lian, Qizhou; Leung, Felix W; Liu, Yufeng; Sha, Weihong; Chen, Hao (2024-05-23). "Unveiling promising drug targets for autism spectrum disorder: insights from genetics, transcriptomics, and proteomics". Briefings in Bioinformatics. 25 (4). doi:10.1093/bib/bbae353. ISSN 1467-5463. PMC 11262832. PMID 39038939.
  10. ^ Gonzales, Samantha; Zhao, Jane Zizhen; Choi, Na Young; Acharya, Prabha; Jeong, Sehoon; Lee, Moo-Yeal (2023-09-14), SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data, doi:10.21203/rs.3.rs-3346245/v1, PMC 10543249, PMID 37790478, retrieved 2024-10-19
  11. ^ Sykes NH, Lamb JA (September 2007). "Autism: the quest for the genes". Expert Reviews in Molecular Medicine. 9 (24): 1–15. doi:10.1017/S1462399407000452. PMID 17764594. S2CID 45880191.
  12. ^ Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017-05-22). "Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia". Molecular Autism. 8 (1): 21. doi:10.1186/s13229-017-0137-9. ISSN 2040-2392. PMC 5441062. PMID 28540026.
  13. ^ Persico AM, Bourgeron T (July 2006). "Searching for ways out of the autism maze: genetic, epigenetic and environmental clues". Trends in Neurosciences. 29 (7): 349–358. doi:10.1016/j.tins.2006.05.010. PMID 16808981. S2CID 26722022.
  14. ^ Yang MS, Gill M (April 2007). "A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence". International Journal of Developmental Neuroscience. 25 (2): 69–85. doi:10.1016/j.ijdevneu.2006.12.002. PMID 17236739. S2CID 39503634.
  15. ^ Cohen D, Pichard N, Tordjman S, Baumann C, Burglen L, Excoffier E, et al. (February 2005). "Specific genetic disorders and autism: clinical contribution towards their identification". Journal of Autism and Developmental Disorders. 35 (1): 103–16. doi:10.1007/s10803-004-1038-2. PMID 15796126. S2CID 2101244.
  16. ^ Müller RA (2007). "The study of autism as a distributed disorder". Mental Retardation and Developmental Disabilities Research Reviews. 13 (1): 85–95. doi:10.1002/mrdd.20141. PMC 3315379. PMID 17326118.
  17. ^ Cook EH, Scherer SW (October 2008). "Copy-number variations associated with neuropsychiatric conditions". Nature. 455 (7215): 919–923. Bibcode:2008Natur.455..919C. doi:10.1038/nature07458. PMID 18923514. S2CID 4377899.
  18. ^ Gai X, Xie HM, Perin JC, Takahashi N, Murphy K, Wenocur AS, et al. (April 2012). "Rare structural variation of synapse and neurotransmission genes in autism". Molecular Psychiatry. 17 (4): 402–411. doi:10.1038/mp.2011.10. PMC 3314176. PMID 21358714.
  19. ^ Devlin B, Scherer SW (June 2012). "Genetic architecture in autism spectrum disorder". Current Opinion in Genetics & Development. Molecular and genetic bases of disease. 22 (3): 229–237. doi:10.1016/j.gde.2012.03.002. PMID 22463983.
  20. ^ Sztainberg Y, Zoghbi HY (October 2016). "Lessons learned from studying syndromic autism spectrum disorders". Nature Neuroscience. 19 (11): 1408–1417. doi:10.1038/nn.4420. PMID 27786181. S2CID 3332899.
  21. ^ Benvenuto A, Moavero R, Alessandrelli R, Manzi B, Curatolo P (August 2009). "Syndromic autism: causes and pathogenetic pathways". World Journal of Pediatrics. 5 (3): 169–176. doi:10.1007/s12519-009-0033-2. PMID 19693459. S2CID 27851799.
  22. ^ a b c Beaudet AL (May 2007). "Autism: highly heritable but not inherited". Nature Medicine. 13 (5): 534–6. doi:10.1038/nm0507-534. PMID 17479094. S2CID 11673879.
  23. ^ Tabor HK, Cho MK (September 2007). "Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research". Genetics in Medicine. 9 (9): 626–31. doi:10.1097/GIM.0b013e3181485688. PMC 2220022. PMID 17873651.
  24. ^ a b Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, et al. (March 2007). "Mapping autism risk loci using genetic linkage and chromosomal rearrangements". Nature Genetics. 39 (3): 319–28. doi:10.1038/ng1985. PMC 4867008. PMID 17322880. "Corrigendum". Nat Genet. 39 (10): 1285. 2007. doi:10.1038/ng1007-1285a.
  25. ^ Liu XQ, Paterson AD, Szatmari P (October 2008). "Genome-wide linkage analyses of quantitative and categorical autism subphenotypes". Biological Psychiatry. 64 (7): 561–70. doi:10.1016/j.biopsych.2008.05.023. PMC 2670970. PMID 18632090.
  26. ^ Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ (June 2005). "Genetic influences in irritable bowel syndrome: a twin study". The American Journal of Gastroenterology. 100 (6): 1340–4. doi:10.1111/j.1572-0241.2005.41700.x. PMID 15929767. S2CID 24085444.
  27. ^ Bito LZ, Matheny A, Cruickshanks KJ, Nondahl DM, Carino OB (May 1997). "Eye color changes past early childhood. The Louisville Twin Study". Archives of Ophthalmology. 115 (5): 659–63. doi:10.1001/archopht.1997.01100150661017. PMID 9152135.
  28. ^ Twin studies (concordance in brackets):
  29. ^ Folstein S, Rutter M (September 1977). "Infantile autism: a genetic study of 21 twin pairs". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 18 (4): 297–321. doi:10.1111/j.1469-7610.1977.tb00443.x. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 562353.
  30. ^ Wessels WH, Pompe van Meerdervoort M (June 1979). "Monozygotic twins with early infantile autism. A case report". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde. 55 (23): 955–7. PMID 572995.
  31. ^ Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM (January 1985). "Concordance for the syndrome of autism in 40 pairs of afflicted twins". The American Journal of Psychiatry. 142 (1): 74–7. doi:10.1176/ajp.142.1.74. PMID 4038442.
  32. ^ Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M (May 1989). "A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 30 (3): 405–16. doi:10.1111/j.1469-7610.1989.tb00254.x. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 2745591.
  33. ^ a b c Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (January 1995). "Autism as a strongly genetic disorder: evidence from a British twin study". Psychological Medicine. 25 (1): 63–77. doi:10.1017/S0033291700028099. PMID 7792363. S2CID 28907073.
  34. ^ Scourfield J, Martin N, Lewis G, McGuffin P (December 1999). "Heritability of social cognitive skills in children and adolescents". The British Journal of Psychiatry. 175 (6): 559–64. doi:10.1192/bjp.175.6.559. PMID 10789354. S2CID 38743852.
  35. ^ Constantino JN, Todd RD (December 2000). "Genetic structure of reciprocal social behavior". The American Journal of Psychiatry. 157 (12): 2043–5. doi:10.1176/appi.ajp.157.12.2043. PMID 11097975.
  36. ^ Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, et al. (March 2004). "Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism". The American Journal of Psychiatry. 161 (3): 539–46. doi:10.1176/appi.ajp.161.3.539. PMID 14992981.
  37. ^ Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM (August 2004). "Familial symptom domains in monozygotic siblings with autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 129B (1): 76–81. doi:10.1002/ajmg.b.30011. PMID 15274045. S2CID 31012683.
  38. ^ Ronald A, Happé F, Bolton P, Butcher LM, Price TS, Wheelwright S, et al. (June 2006). "Genetic heterogeneity between the three components of the autism spectrum: a twin study". Journal of the American Academy of Child and Adolescent Psychiatry. 45 (6): 691–699. doi:10.1097/01.chi.0000215325.13058.9d. PMID 16721319.
  39. ^ Joseph J (2006). "Autism and genetics: much ado about very little". The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes. Algora. ISBN 0-87586-410-4. Archived from the original on 2007-09-27. Retrieved 2007-07-25.
  40. ^ Hughes C, Plumet MH, Leboyer M (July 1999). "Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 40 (5): 705–18. doi:10.1111/1469-7610.00487. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 10433405.
  41. ^ Lauritsen MB, Pedersen CB, Mortensen PB (September 2005). "Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 46 (9): 963–71. doi:10.1111/j.1469-7610.2004.00391.x. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 16108999.
  42. ^ a b Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, et al. (July 2007). "A unified genetic theory for sporadic and inherited autism". Proceedings of the National Academy of Sciences of the United States of America. 104 (31): 12831–6. Bibcode:2007PNAS..10412831Z. doi:10.1073/pnas.0705803104. PMC 1933261. PMID 17652511.
  43. ^ Piven J, Wzorek M, Landa R, Lainhart J, Bolton P, Chase GA, Folstein S (August 1994). "Personality characteristics of the parents of autistic individuals". Psychological Medicine. 24 (3): 783–95. doi:10.1017/S0033291700027938. PMID 7991760. S2CID 20725041.
  44. ^ Piven J, Palmer P, Jacobi D, Childress D, Arndt S (February 1997). "Broader autism phenotype: evidence from a family history study of multiple-incidence autism families". The American Journal of Psychiatry. 154 (2): 185–90. doi:10.1176/ajp.154.2.185. PMID 9016266.
  45. ^ Baron-Cohen S, Bolton P, Wheelwright S, Short L, Mead G, Smith A, Scahill V (1998). "Autism occurs more often in families of physicists, engineers, and mathematicians" (PDF). Autism. 2 (3): 296–301. doi:10.1177/1362361398023008. S2CID 146452233. Archived from the original (PDF) on 2006-05-05.
  46. ^ Baron-Cohen S, Wheelwright S, Stott C, Bolton P, Goodyer I (1997). "Is there a link between engineering and autism?" (PDF). Autism. 1 (1): 153–163. doi:10.1177/1362361397011010. S2CID 145375886. Archived from the original (PDF) on 2006-05-05.
  47. ^ Wheelwright S, Baron-Cohen S (June 2001). "The link between autism and skills such as engineering, maths, physics and computing: a reply to Jarrold and Routh". Autism. 5 (2): 223–7. doi:10.1177/1362361301005002010. PMID 11706868. S2CID 14554953. Archived from the original on October 5, 2020. Retrieved October 5, 2020.
  48. ^ Silberman S (December 2001). "The Geek Syndrome". Wired Magazine. Archived from the original on 2001-12-18. Retrieved December 10, 2006.
  49. ^ Happé F, Briskman J, Frith U (March 2001). "Exploring the cognitive phenotype of autism: weak "central coherence" in parents and siblings of children with autism: I. Experimental tests". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 42 (3): 299–307. doi:10.1111/1469-7610.00723. eISSN 1469-7610. ISSN 0021-9630. OCLC 01307942. PMID 11321199.
  50. ^ Abramson RK, Ravan SA, Wright HH, Wieduwilt K, Wolpert CM, Donnelly SA, et al. (2005). "The relationship between restrictive and repetitive behaviors in individuals with autism and obsessive compulsive symptoms in parents". Child Psychiatry and Human Development. 36 (2): 155–65. doi:10.1007/s10578-005-2973-7. PMID 16228144. S2CID 44501937.
  51. ^ Constantino JN, Todd RD (March 2005). "Intergenerational transmission of subthreshold autistic traits in the general population". Biological Psychiatry. 57 (6): 655–60. doi:10.1016/j.biopsych.2004.12.014. PMID 15780853. S2CID 7623717.
  52. ^ Ghaziuddin M (April 2005). "A family history study of Asperger syndrome". Journal of Autism and Developmental Disorders. 35 (2): 177–82. doi:10.1007/s10803-004-1996-4. hdl:2027.42/44625. PMID 15909404. S2CID 16544247.
  53. ^ "Half of Moms of Kids With Autism Have High Depressive Symptoms". August 26, 2022.
  54. ^ Greenberg DA, Hodge SE, Sowinski J, Nicoll D (November 2001). "Excess of twins among affected sibling pairs with autism: implications for the etiology of autism". American Journal of Human Genetics. 69 (5): 1062–7. doi:10.1086/324191. PMC 1274353. PMID 11590546.
  55. ^ a b c d e Hallmayer J, Glasson EJ, Bower C, Petterson B, Croen L, Grether J, Risch N (October 2002). "On the twin risk in autism". American Journal of Human Genetics. 71 (4): 941–6. doi:10.1086/342990. PMC 378547. PMID 12297988.
  56. ^ Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. (November 2014). "The contribution of de novo coding mutations to autism spectrum disorder". Nature. 515 (7526): 216–21. Bibcode:2014Natur.515..216I. doi:10.1038/nature13908. PMC 4313871. PMID 25363768.
  57. ^ Gringras P, Chen W (September 2001). "Mechanisms for differences in monozygous twins". Early Human Development. 64 (2): 105–17. doi:10.1016/S0378-3782(01)00171-2. PMID 11440823.
  58. ^ a b c Brandler WM, Sebat J (14 January 2015). "From de novo mutations to personalized therapeutic interventions in autism". Annual Review of Medicine. 66 (1): 487–507. doi:10.1146/annurev-med-091113-024550. PMID 25587659.
  59. ^ Ronemus M, Iossifov I, Levy D, Wigler M (February 2014). "The role of de novo mutations in the genetics of autism spectrum disorders". Nature Reviews. Genetics. 15 (2): 133–41. doi:10.1038/nrg3585. PMID 24430941. S2CID 9073763.
  60. ^ "SFARI CNV". Archived from the original on 2016-03-29. Retrieved 2016-03-19.
  61. ^ "SFARI gene scoring module". Archived from the original on 2016-03-28. Retrieved 2016-03-19.
  62. ^ Shchelochkov, Oleg A.; Farmer, Cristan A.; Chlebowski, Colby; Adedipe, Dee; Ferry, Susan; Manoli, Irini; Pass, Alexandra; McCoy, Samantha; Van Ryzin, Carol; Sloan, Jennifer; Thurm, Audrey; Venditti, Charles P. (2024-01-11). "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology". Molecular Psychiatry: 1–8. doi:10.1038/s41380-023-02385-5. ISSN 1476-5578. PMC 11176071.
  63. ^ a b Levitt P, Campbell DB (April 2009). "The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders". The Journal of Clinical Investigation. 119 (4): 747–54. doi:10.1172/JCI37934. PMC 2662567. PMID 19339766.
  64. ^ a b Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, et al. (May 2010). "Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size". Journal of Medical Genetics. 47 (5): 332–41. doi:10.1136/jmg.2009.073015. PMC 3158566. PMID 19914906.
  65. ^ a b Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, Ledbetter DH (April 2013). "Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence". The Lancet. Neurology. 12 (4): 406–14. doi:10.1016/S1474-4422(13)70011-5. PMC 4013791. PMID 23518333.
  66. ^ McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, et al. (November 2009). "Microduplications of 16p11.2 are associated with schizophrenia". Nature Genetics. 41 (11): 1223–7. doi:10.1038/ng.474. PMC 2951180. PMID 19855392.
  67. ^ The Simons Vip Consortium (March 2012). "Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders". Neuron. 73 (6): 1063–7. doi:10.1016/j.neuron.2012.02.014. PMID 22445335. S2CID 2687724.
  68. ^ Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, et al. (January 2014). "CNVs conferring risk of autism or schizophrenia affect cognition in controls". Nature. 505 (7483): 361–6. Bibcode:2014Natur.505..361S. doi:10.1038/Nature12818. hdl:2336/311615. PMID 24352232. S2CID 3842341. Archived from the original on 5 October 2020.
  69. ^ a b Wittkowski KM, Sonakya V, Bigio B, Tonn MK, Shic F, Ascano M, et al. (January 2014). "A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism". Translational Psychiatry. 4 (1): e354. doi:10.1038/tp.2013.124. PMC 3905234. PMID 24473445.
  70. ^ Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, et al. (November 2004). "A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A". American Journal of Medical Genetics. Part A. 131 (1): 1–10. doi:10.1002/ajmg.a.30297. PMID 15389703. S2CID 9570482.
  71. ^ Schanen NC (October 2006). "Epigenetics of autism spectrum disorders". Human Molecular Genetics. 15 (Review 2): R138-50. doi:10.1093/hmg/ddl213. PMID 16987877. Archived from the original on 2007-10-09.
  72. ^ Skuse DH (January 2000). "Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism". Pediatric Research. 47 (1): 9–16. doi:10.1203/00006450-200001000-00006. PMID 10625077. S2CID 3140415.
  73. ^ Crespi B, Badcock C (June 2008). "Psychosis and autism as diametrical disorders of the social brain" (PDF). The Behavioral and Brain Sciences. 31 (3): 241–61, discussion 261–320. doi:10.1017/S0140525X08004214. PMID 18578904. Archived from the original (PDF) on 2020-04-12.
  74. ^ Trottier G, Srivastava L, Walker CD (March 1999). "Etiology of infantile autism: a review of recent advances in genetic and neurobiological research". Journal of Psychiatry & Neuroscience. 24 (2): 103–15. PMC 1188990. PMID 10212552.
  75. ^ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". International Journal of Developmental Neuroscience. 23 (2–3): 189–99. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245. S2CID 17797266.
  76. ^ Rutter M (January 2005). "Incidence of autism spectrum disorders: changes over time and their meaning". Acta Paediatrica. 94 (1): 2–15. doi:10.1111/j.1651-2227.2005.tb01779.x. PMID 15858952. S2CID 79259285.
  77. ^ Szpir M (July 2006). "Tracing the origins of autism: a spectrum of new studies". Environmental Health Perspectives. 114 (7): A412-8. doi:10.1289/ehp.114-a412. PMC 1513312. PMID 16835042. Archived from the original on 2008-07-08.
  78. ^ a b c d e f g h "Gene linked to sex differences in autism". National Institutes of Health (NIH). NIH Research Matters. U.S. Department of Health and Human Services. 2020-04-13. Archived from the original on 2022-06-09. Retrieved 2022-02-28.
  79. ^ a b Loomes R, Hull L, Mandy WP (June 2017). "What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis". Journal of the American Academy of Child and Adolescent Psychiatry. 56 (6): 466–474. doi:10.1016/j.jaac.2017.03.013. PMID 28545751. S2CID 20420861.
  80. ^ Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, et al. (July 2007). "A unified genetic theory for sporadic and inherited autism". Proceedings of the National Academy of Sciences of the United States of America. 104 (31): 12831–12836. Bibcode:2007PNAS..10412831Z. doi:10.1073/pnas.0705803104. PMC 1933261. PMID 17652511.
  81. ^ a b c d e Nguyen TA, Wu K, Pandey S, Lehr AW, Li Y, Bemben MA, et al. (June 2020). "A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y". Neuron. 106 (5): 759–768.e7. doi:10.1016/j.neuron.2020.03.008. PMC 7491604. PMID 32243781.
  82. ^ a b c Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, et al. (May 2003). "Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism". Nature Genetics. 34 (1): 27–29. doi:10.1038/ng1136. PMC 1925054. PMID 12669065.
  83. ^ Benvenuto A, Manzi B, Alessandrelli R, Galasso C, Curatolo P (2009). "Recent advances in the pathogenesis of syndromic autisms". International Journal of Pediatrics. 2009: 198736. doi:10.1155/2009/198736. PMC 2778501. PMID 19946417.
  84. ^ Wall DP, Esteban FJ, Deluca TF, Huyck M, Monaghan T, Velez de Mendizabal N, et al. (February 2009). "Comparative analysis of neurological disorders focuses genome-wide search for autism genes". Genomics. 93 (2): 120–9. doi:10.1016/j.ygeno.2008.09.015. PMID 18950700.
  85. ^ Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, et al. (May 2009). "Common genetic variants on 5p14.1 associate with autism spectrum disorders". Nature. 459 (7246): 528–33. Bibcode:2009Natur.459..528W. doi:10.1038/nature07999. PMC 2943511. PMID 19404256.
  86. ^ Pagnamenta AT, Khan H, Walker S, Gerrelli D, Wing K, Bonaglia MC, et al. (January 2011). "Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability". Journal of Medical Genetics. 48 (1): 48–54. doi:10.1136/jmg.2010.079426. PMC 3003876. PMID 20972252.
  87. ^ a b Brandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, et al. (April 2016). "Frequency and Complexity of De Novo Structural Mutation in Autism". American Journal of Human Genetics. 98 (4): 667–79. doi:10.1016/j.ajhg.2016.02.018. PMC 4833290. PMID 27018473.
  88. ^ Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, et al. (February 2008). "Association between microdeletion and microduplication at 16p11.2 and autism". The New England Journal of Medicine. 358 (7): 667–75. doi:10.1056/NEJMoa075974. PMID 18184952.
  89. ^ Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. (February 2008). "Structural variation of chromosomes in autism spectrum disorder". American Journal of Human Genetics. 82 (2): 477–88. doi:10.1016/j.ajhg.2007.12.009. PMC 2426913. PMID 18252227. Archived from the original on 2013-02-23.
  90. ^ Samuels IS, Saitta SC, Landreth GE (January 2009). "MAP'ing CNS development and cognition: an ERKsome process". Neuron. 61 (2): 160–7. doi:10.1016/j.neuron.2009.01.001. PMC 3663441. PMID 19186160.
  91. ^ Surtees PG, Wainwright NW, Willis-Owen SA, Luben R, Day NE, Flint J (February 2006). "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder". Biological Psychiatry. 59 (3): 224–9. doi:10.1016/j.biopsych.2005.07.014. PMID 16154545. S2CID 9123655.
  92. ^ Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, et al. (August 2005). "Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors". American Journal of Human Genetics. 77 (2): 265–79. doi:10.1086/432648. PMC 1224529. PMID 15995945.
  93. ^ Devlin B, Cook EH, Coon H, Dawson G, Grigorenko EL, McMahon W, et al. (December 2005). "Autism and the serotonin transporter: the long and short of it". Molecular Psychiatry. 10 (12): 1110–6. doi:10.1038/sj.mp.4001724. PMID 16103890. S2CID 25595611.
  94. ^ Coutinho AM, Oliveira G, Morgadinho T, Fesel C, Macedo TR, Bento C, et al. (March 2004). "Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism". Molecular Psychiatry. 9 (3): 264–71. doi:10.1038/sj.mp.4001409. PMID 15094787. S2CID 6754384.
  95. ^ Huang CH, Santangelo SL (September 2008). "Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 147B (6): 903–13. doi:10.1002/ajmg.b.30720. PMID 18286633. S2CID 9491697.
  96. ^ Strom SP, Stone JL, Ten Bosch JR, Merriman B, Cantor RM, Geschwind DH, Nelson SF (October 2010). "High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene". Molecular Psychiatry. 15 (10): 996–1005. doi:10.1038/mp.2009.41. PMC 2889141. PMID 19455149.
  97. ^ Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, et al. (September 2005). "Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism". American Journal of Human Genetics. 77 (3): 377–88. doi:10.1086/433195. PMC 1226204. PMID 16080114.
  98. ^ Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS (July 2003). "Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13". Journal of the American Academy of Child and Adolescent Psychiatry. 42 (7): 856–63. doi:10.1097/01.CHI.0000046868.56865.0F. PMID 12819446.
  99. ^ DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (March 2008). "Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder". Behavioural Brain Research. 187 (2): 207–20. doi:10.1016/j.bbr.2007.09.009. PMC 2684890. PMID 17983671.
  100. ^ Benayed R, Gharani N, Rossman I, Mancuso V, Lazar G, Kamdar S, et al. (November 2005). "Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus". American Journal of Human Genetics. 77 (5): 851–68. doi:10.1086/497705. PMC 1271392. PMID 16252243.
  101. ^ Zhong H, Serajee FJ, Nabi R, Huq AH (January 2003). "No association between the EN2 gene and autistic disorder". Journal of Medical Genetics. 40 (1): 4e–4. doi:10.1136/jmg.40.1.e4. PMC 1735256. PMID 12525552.
  102. ^ Auranen M, Varilo T, Alen R, Vanhala R, Ayers K, Kempas E, et al. (October 2003). "Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland". Molecular Psychiatry. 8 (10): 879–84. doi:10.1038/sj.mp.4001299. PMID 14515138. S2CID 2923001.
  103. ^ Ylisaukko-oja T, Nieminen-von Wendt T, Kempas E, Sarenius S, Varilo T, von Wendt L, et al. (February 2004). "Genome-wide scan for loci of Asperger syndrome". Molecular Psychiatry. 9 (2): 161–8. doi:10.1038/sj.mp.4001385. PMID 14966474. S2CID 22601412.
  104. ^ Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T, et al. (October 2002). "A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27". American Journal of Human Genetics. 71 (4): 777–90. doi:10.1086/342720. PMC 378535. PMID 12192642.
  105. ^ Serajee FJ, Zhong H, Mahbubul Huq AH (January 2006). "Association of Reelin gene polymorphisms with autism". Genomics. 87 (1): 75–83. doi:10.1016/j.ygeno.2005.09.008. PMID 16311013.
  106. ^ Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER, et al. (June 2005). "Analysis of the RELN gene as a genetic risk factor for autism". Molecular Psychiatry. 10 (6): 563–71. doi:10.1038/sj.mp.4001614. PMID 15558079. S2CID 324756.
  107. ^ Li J, Nguyen L, Gleason C, Lotspeich L, Spiker D, Risch N, Myers RM (April 2004). "Lack of evidence for an association between WNT2 and RELN polymorphisms and autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 126B (1): 51–7. doi:10.1002/ajmg.b.20122. PMID 15048648. S2CID 19378694.
  108. ^ Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L (November 2005). "Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31". The American Journal of Psychiatry. 162 (11): 2182–4. doi:10.1176/appi.ajp.162.11.2182. hdl:2262/34993. PMID 16263864.
  109. ^ Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD (April 2004). "Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism". The American Journal of Psychiatry. 161 (4): 662–9. doi:10.1176/appi.ajp.161.4.662. PMID 15056512.
  110. ^ Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, et al. (April 2008). "SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects". Molecular Psychiatry. 13 (4): 385–97. doi:10.1038/sj.mp.4002120. PMID 18180767. S2CID 28912813.
  111. ^ Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E (January 2006). "SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample". European Journal of Human Genetics. 14 (1): 123–6. doi:10.1038/sj.ejhg.5201444. PMID 16205742. S2CID 12440829.
  112. ^ Kent L, Gallagher L, Elliott HR, Mowbray C, Chinnery PF (September 2008). "An investigation of mitochondrial haplogroups in autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 147B (6): 987–9. doi:10.1002/ajmg.b.30687. PMID 18161860. S2CID 1956544.
  113. ^ Rodier PM (February 2000). "The early origins of autism". Scientific American. 282 (2): 56–63. Bibcode:2000SciAm.282b..56R. doi:10.1038/scientificamerican0200-56. PMID 10710787.
  114. ^ Conciatori M, Stodgell CJ, Hyman SL, O'Bara M, Militerni R, Bravaccio C, et al. (February 2004). "Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism". Biological Psychiatry. 55 (4): 413–9. doi:10.1016/j.biopsych.2003.10.005. PMID 14960295. S2CID 6903399.
  115. ^ Gallagher L, Hawi Z, Kearney G, Fitzgerald M, Gill M (January 2004). "No association between allelic variants of HOXA1/HOXB1 and autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 124B (1): 64–7. doi:10.1002/ajmg.b.20094. PMID 14681917. S2CID 36366275.
  116. ^ Collins JS, Schroer RJ, Bird J, Michaelis RC (June 2003). "The HOXA1 A218G polymorphism and autism: lack of association in white and black patients from the South Carolina Autism Project". Journal of Autism and Developmental Disorders. 33 (3): 343–8. doi:10.1023/A:1024414803151. PMID 12908836. S2CID 46207102.
  117. ^ Talebizadeh Z, Bittel DC, Miles JH, Takahashi N, Wang CH, Kibiryeva N, Butler MG (November 2002). "No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD)". Journal of Medical Genetics. 39 (11): 70e–70. doi:10.1136/jmg.39.11.e70. PMC 1735009. PMID 12414832.
  118. ^ Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, et al. (October 2005). "Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development". Nature Genetics. 37 (10): 1035–7. doi:10.1038/ng1636. PMID 16155570. S2CID 12062207.
  119. ^ Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM (December 2000). "Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders". Teratology. 62 (6): 393–405. doi:10.1002/1096-9926(200012)62:6<393::AID-TERA6>3.0.CO;2-V. PMID 11091361.
  120. ^ Rossel M, Capecchi MR (November 1999). "Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development". Development. 126 (22): 5027–40. doi:10.1242/dev.126.22.5027. PMID 10529420.
  121. ^ Roullet FI, Lai JK, Foster JA (2013). "In utero exposure to valproic acid and autism--a current review of clinical and animal studies". Neurotoxicology and Teratology. 36: 47–56. doi:10.1016/j.ntt.2013.01.004. PMID 23395807.
  122. ^ Philippi A, Roschmann E, Tores F, Lindenbaum P, Benajou A, Germain-Leclerc L, et al. (October 2005). "Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism". Molecular Psychiatry. 10 (10): 950–60. doi:10.1038/sj.mp.4001704. PMID 16027742. S2CID 23930885.
  123. ^ Richter M, Murtaza N, Scharrenberg R, White SH, Johanns O, Walker S, et al. (September 2019). "Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling". Molecular Psychiatry. 24 (9): 1329–1350. doi:10.1038/s41380-018-0025-5. PMC 6756231. PMID 29467497.
  124. ^ Medina JJ (2009). "Fishing for genetic links in autism". Psychiatr Times. 26 (3). Archived from the original on 2009-04-14. Retrieved 2009-07-03.
  125. ^ a b Hogart A, Wu D, LaSalle JM, Schanen NC (May 2010). "The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13". Neurobiology of Disease. 38 (2): 181–91. doi:10.1016/j.nbd.2008.08.011. PMC 2884398. PMID 18840528.
  126. ^ Schuetz G, Rosário M, Grimm J, Boeckers TM, Gundelfinger ED, Birchmeier W (December 2004). "The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells". The Journal of Cell Biology. 167 (5): 945–52. doi:10.1083/jcb.200404108. PMC 2172453. PMID 15569713.
  127. ^ a b c Phelan MC (2003). "Deletion 22q13 Syndrome" (PDF). Ophanet.com. Archived from the original (PDF) on 2007-06-14.
  128. ^ a b Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. (January 2007). "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nature Genetics. 39 (1): 25–7. doi:10.1038/ng1933. PMC 2082049. PMID 17173049.
  129. ^ Harris K (2001). "Neuroligins". Cell adhesion at synapses Synapse Web, Laboratory of Synapse Structure and Function. Human Brain Project. National Institute of Mental Health and the National Institute of Drug Abuse. Archived from the original on 2007-07-27.
  130. ^ Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM (December 2004). "Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins". Cell. 119 (7): 1013–26. doi:10.1016/j.cell.2004.11.035. PMC 2826211. PMID 15620359.
  131. ^ Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC (October 2007). "A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice". Science. 318 (5847): 71–6. Bibcode:2007Sci...318...71T. doi:10.1126/science.1146221. PMC 3235367. PMID 17823315.
  132. ^ Wermter AK, Kamp-Becker I, Strauch K, Schulte-Körne G, Remschmidt H (June 2008). "No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 147B (4): 535–7. doi:10.1002/ajmg.b.30618. PMID 18189281. S2CID 205324352.
  133. ^ a b "Gene Linked to Autism in Families with More Than One Affected Child". National Institute of Mental Health, & National Institute of Child Health and Human Development. National Institutes of Health News. U.S. Department of Health and Human Services. 17 October 2006. Archived from the original on 2007-02-20. Retrieved 3 March 2007.
  134. ^ Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. (November 2006). "A genetic variant that disrupts MET transcription is associated with autism". Proceedings of the National Academy of Sciences of the United States of America. 103 (45): 16834–9. doi:10.1073/pnas.0605296103. PMC 1838551. PMID 17053076.
  135. ^ Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y, et al. (January 2008). "Disruption of neurexin 1 associated with autism spectrum disorder". American Journal of Human Genetics. 82 (1): 199–207. doi:10.1016/j.ajhg.2007.09.011. PMC 2253961. PMID 18179900. Archived from the original on 2008-04-17.
  136. ^ Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, et al. (January 2008). "Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene". American Journal of Human Genetics. 82 (1): 150–9. doi:10.1016/j.ajhg.2007.09.005. PMC 2253955. PMID 18179893. Archived from the original on 2008-01-16.
  137. ^ Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, et al. (January 2008). "A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism". American Journal of Human Genetics. 82 (1): 160–4. doi:10.1016/j.ajhg.2007.09.015. PMC 2253968. PMID 18179894. Archived from the original on 2008-01-16.
  138. ^ Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, et al. (January 2008). "Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders". American Journal of Human Genetics. 82 (1): 165–73. doi:10.1016/j.ajhg.2007.09.017. PMC 2253974. PMID 18179895. Archived from the original on 2008-01-16.
  139. ^ Marui T, Koishi S, Funatogawa I, Yamamoto K, Matsumoto H, Hashimoto O, et al. (September 2005). "No association of FOXP2 and PTPRZ1 on 7q31 with autism from the Japanese population". Neuroscience Research. 53 (1): 91–4. doi:10.1016/j.neures.2005.05.003. PMID 15998549. S2CID 12136762.
  140. ^ Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA (April 2003). "Mutation screening of FOXP2 in individuals diagnosed with autistic disorder". American Journal of Medical Genetics. Part A. 118A (2): 172–5. doi:10.1002/ajmg.a.10105. PMID 12655497. S2CID 39762074.
  141. ^ Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, et al. (November 2008). "A functional genetic link between distinct developmental language disorders". The New England Journal of Medicine. 359 (22): 2337–45. doi:10.1056/NEJMoa0802828. PMC 2756409. PMID 18987363.
  142. ^ Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF, et al. (April 2007). "Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype". Archives of Pediatrics & Adolescent Medicine. 161 (4): 356–61. doi:10.1001/archpedi.161.4.356. PMID 17404132. Archived from the original on 2007-09-29.
  143. ^ LoParo D, Waldman ID (May 2015). "The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis". Molecular Psychiatry. 20 (5): 640–6. doi:10.1038/mp.2014.77. PMID 25092245. S2CID 36296721.
  144. ^ a b Ylisaukko-oja T, Alarcón M, Cantor RM, Auranen M, Vanhala R, Kempas E, et al. (January 2006). "Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families". Annals of Neurology. 59 (1): 145–55. doi:10.1002/ana.20722. PMID 16288458. S2CID 23223861.
  145. ^ Lauritsen MB, Als TD, Dahl HA, Flint TJ, Wang AG, Vang M, et al. (January 2006). "A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands". Molecular Psychiatry. 11 (1): 37–46. doi:10.1038/sj.mp.4001754. PMID 16205737. S2CID 1318464.
  146. ^ Trikalinos TA, Karvouni A, Zintzaras E, Ylisaukko-oja T, Peltonen L, Järvelä I, Ioannidis JP (January 2006). "A heterogeneity-based genome search meta-analysis for autism-spectrum disorders". Molecular Psychiatry. 11 (1): 29–36. doi:10.1038/sj.mp.4001750. PMID 16189507. S2CID 7738080.
  147. ^ Yonan AL, Alarcón M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, et al. (October 2003). "A genomewide screen of 345 families for autism-susceptibility loci". American Journal of Human Genetics. 73 (4): 886–97. doi:10.1086/378778. PMC 1180610. PMID 13680528.
  148. ^ Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcón M, et al. (June 2005). "Replication of autism linkage: fine-mapping peak at 17q21". American Journal of Human Genetics. 76 (6): 1050–6. doi:10.1086/430278. PMC 1196442. PMID 15877280.
  149. ^ Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, et al. (April 2005). "Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations". Journal of Medical Genetics. 42 (4): 318–21. doi:10.1136/jmg.2004.024646. PMC 1736032. PMID 15805158.
  150. ^ Bearden C (2016-10-18). "Same DNA deletion paves paths to autism, schizophrenia". Spectrum. Archived from the original on 2016-11-02. Retrieved 2016-10-18.
  151. ^ Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, et al. (July 2008). "Identifying autism loci and genes by tracing recent shared ancestry". Science. 321 (5886): 218–23. Bibcode:2008Sci...321..218M. doi:10.1126/science.1157657. PMC 2586171. PMID 18621663.
  152. ^ Geschwind DH (August 2008). "Autism: Family connections". Nature. 454 (7206): 838–9. Bibcode:2008Natur.454..838G. doi:10.1038/454838a. PMC 3645842. PMID 18704077.
  153. ^ Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S, et al. (February 2006). "Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number". Science. 311 (5763): 1008–12. Bibcode:2006Sci...311.1008F. doi:10.1126/science.1122511. PMID 16484497. S2CID 13280518.
  154. ^ Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, et al. (July 2008). "Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo". Proceedings of the National Academy of Sciences of the United States of America. 105 (27): 9397–402. Bibcode:2008PNAS..105.9397L. doi:10.1073/pnas.0802876105. PMC 2453715. PMID 18599437.

Further reading

[edit]
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Heritability_of_autism&oldid=1253300580"