Genetic links between autism and typical variation in social behavior and adaptive function

The genetic etiology of autism is starting to become better understood. Common as well as rare variants are known to contribute to risk. ASD exists in the tail of a spectrum of behavioral traits, and sub-threshold traits are more likely to be found in relatives of an individual diagnosed with ASD. The paper reports a genetic correlation of 0.4 between ASD and IQ, which suggests that many ASD variants also affect general cognitive function (Supplement).

See also De novo mutations and autism and Disruptive mutations and the genetic architecture of autism.

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Nature Genetics (2016) doi:10.1038/ng.3529

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

From the paper

... Consistent with traditional approaches to psychiatric phenotypes, most genetic studies of ASDs compare cases to controls to identify risk-associated variation. This approach has been highly productive— recent studies have linked common polygenic as well as de novo and inherited rare variation to ASD risk1,2. Common genotyped SNPs are estimated to account for at least 20% of ASD liability1,3,4. Contributing de novo variants are found in 10–20% of cases, but de novo mutations collectively explain less than 5% of overall ASD liability1,5,6.

Almost all genetic risk factors for ASDs can be found in unaffected individuals. For example, most people who carry a 16p11.2 deletion, the most common large mutational risk factor for ASDs, do not meet the criteria for an ASD diagnosis7. Across healthy populations, there is also substantial variability in capacity for social interaction and social communication8. Although such phenotypic variation is well established, the genetic relationship between neuropsychiatric disorders and typical social and behavioral variation remains unclear. From the first published descriptions of ASDs, clinical and epidemiological reports have commonly noted subthreshold traits of autism in the family members of many diagnosed individuals9,10. Twin and family studies have suggested that these similarities are at least in part inherited and also suggest that traits and diagnosis are correlated genetically11–13, but the correlation has yet to be estimated using measured genetic data.

... These data strongly suggest that genetic influences on ASD risk—both inherited and de novo—influence typical variation in the population in social and communication ability. They also link clinically significant problems to impairments that are less likely to be ascertained. The results have major implications for genetic models of neuropsychiatric disorder risk. It is likely that inherited liability for ASDs is reflected in the behavioral traits of some family members of affected individuals. This links genetic and phenotypic burden in an intuitively consistent fashion with complex, continuously distributed polygenic disease risk. For traits such as height, it is simple to conceptualize a model in which tall parents (for example, those with a height 2 s.d. above the mean) are more likely to have a child who is very tall (for example, one with a height 3 s.d. above the mean). Historically, this concept has been more complicated in neuropsychiatric disorders. Despite extensive evi- dence, some have even questioned the role of inheritance given that the parents of individuals with ASDs or schizophrenia rarely carry a diagnosis themselves. These results suggest that familiality should be studied in a manner beyond a count of categorically affected family members and that trait variation in controls can provide insight into the underlying etiology of severe neurodevelopmental and psychiatric disorders. The behavioral influence of de novo and inherited genetic risk for ASDs can be quantified, and studies assessing continuous trait variation are likely better equipped to examine the phenotypic correlates of neuropsychiatric disease risk.