title: Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder.
abstract: The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10-4). Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11-1.8, p = 9.56*10-7). Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10-4). Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10-5 and p = 3*10-5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10-12), synapse organization (GO:0050808, p = 8.29*10-7), and axon guidance (GO:0007411, p = 1.81*10-7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability.
authors.affiliation: Department of Psychiatry, Yale School of Medicine, West Haven, Connecticut, United States of America.|VA CT Healthcare Center, West Haven, Connecticut, United States of America.
authors.forename: Renato
authors.identifier: 0000-0003-0745-6046
authors.initials: R
authors.lastname: Polimanti
authors.affiliation: Department of Psychiatry, Yale School of Medicine, West Haven, Connecticut, United States of America.|VA CT Healthcare Center, West Haven, Connecticut, United States of America.|Departments of Genetics, Yale School of Medicine, New Haven, Connecticut, United States of America.|Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Joel
authors.identifier: 0000-0002-4067-1859
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics; D001921:Brain / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003865:Major Depressive Disorder / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D023281:Genomics / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D010902:Pituitary Gland / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D059467:Transcriptome