The genetic architecture of autism spectrum disorders (ASDs) and the potential importance of common regulatory genetic variants

Abstract

Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disorders (ASDs), due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants (CNVs) are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic mutations. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identify many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identification will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance (AEI) of mRNA expression for identifying cis-acting regulatory variants that contribute to ASDs. Saffen D. The genetic architecture of autism spectrum disorders (ASDs) and the potential importance of common regulatory genetic variants. Sci China Life Sci, 2015, 58: 968 -975,

X-CNV: genome-wide prediction of the pathogenicity of copy number variations

“…CNVs are believed to originate via diverse mutational mechanisms such as errors in replication, meiotic recombination, and repair of double-strand breaks [2]. Evidence has mounted that CNVs make a significant contribution to rare variants involved in rare diseases [3][4][5][6] and more common diseases such as cancers [7,8] and neurodevelopmental disorders [9][10][11].…”

Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology

“…Finally, polygenic risk scores encompassing ASD, schizophrenia, and years of educational attainment have been recently shown to be unambiguously associated with ASD and to also contribute to the phenotype in the cases of patients carrying de novo deleterious mutations [16]. The second pattern of genetic variants contributing to ASD reflects the effect of rare, highly penetrant mutations or CNVs that are inherited or, more frequently, arise de novo in the germinal cells; being affected by negative selection because of their detrimental impact on reproductive fitness, their frequency in the general population remains very low [22]. Given the described difficulties in pinpointing common variants related to its onset, progress in ASD genetic research has so far advanced mainly with the discovery of rare, de novo, germline, coding, heterozygous mutations.…”

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

“…The ERBB3 gene encodes a protein in the EGFR family that functions as a heterodimer with other EGFR family members (87). The SNP rs2292239, located in intron 7 of ERBB3, is associated with T1DM, residual beta-cell function and metabolic control (88)(89)(90). Previous studies focused on this gene reported that it confers a risk for T1DM by modulating APC function to exert immunoregulatory effects (91).…”

“…Previous studies focused on this gene reported that it confers a risk for T1DM by modulating APC function to exert immunoregulatory effects (91). A later study demonstrated that ERBB3 also affects beta-cell apoptosis (89). ERBB3 knockdown decreases basal and cytokineinduced apoptosis, but ERBB3 expression is downregulated by proinflammatory cytokines, indicating that this gene may participate in negative regulation by cytokines (89).…”

“…A later study demonstrated that ERBB3 also affects beta-cell apoptosis (89). ERBB3 knockdown decreases basal and cytokineinduced apoptosis, but ERBB3 expression is downregulated by proinflammatory cytokines, indicating that this gene may participate in negative regulation by cytokines (89). Thus, further investigation is needed to resolve the contradiction that the ERBB3 gene is downregulated by proinflammatory cytokines but increases cytokine-induced apoptosis.…”