
Abstract Background Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common and rare variation, with study designs independently targeting each. Meta-analysis within each of these study designs is routine, whether using raw data or summary statistics, but combining results across study designs is atypical. However, tests of functional convergence are used across all study designs, where candidate gene sets are assessed for overlaps with previously known properties. This suggests one possible avenue for combining not study data, but the functional conclusions that they reach. Method In this work, we test for functional convergence in autism spectrum disorder (ASD) across different study types, and specifically whether the degree to which a gene is implicated in autism is correlated with the degree to which it drives functional convergence. Because different study designs are distinguishable by their differences in effect size, this also provides a unified means of incorporating the impact of study design into the analysis of convergence. Results We detected remarkably significant positive trends in aggregate (p < 2.2e-16) with 14 individually significant properties (FDR<0.01), many in areas researchers have targeted based on different reasoning, such as the fragile X mental retardation protein (FMRP) interactor enrichment (FDR 0.003). We are also able to detect novel technical effects and we see that network enrichment from protein-protein interaction data is heavily confounded with study design, arising readily in control data. Conclusions We see a convergent functional signal for a subset of known and novel functions in ASD from all sources of genetic variation. Meta-analytic approaches explicitly accounting for different study designs can be adapted to other diseases to discover novel functional associations and increase statistical power.
Male, 570, anzsrc-for: 0604 Genetics, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), 1.1 Normal biological development and functioning, 610, QH426-470, anzsrc-for: 1103 Clinical Sciences, 3105 Genetics, Loss-of-function, Fragile X Mental Retardation Protein, Genetic, Meta-Analysis as Topic, Models, Recurrence, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Rare variation, Polymorphism, anzsrc-for: 31 Biological Sciences, Autism spectrum disorder, Pediatric, Fragile X Messenger Ribonucleoprotein 1, Polymorphism, Genetic, Models, Genetic, Research, Human Genome, R, Genomics, Brain Disorders, Gene candidate score, Meta-analysis, anzsrc-for: 3105 Genetics, Common variation, Mental Health, Effect sizes, Neurological, Mutation, Medicine, Female, Functional enrichment, 31 Biological Sciences
Male, 570, anzsrc-for: 0604 Genetics, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), 1.1 Normal biological development and functioning, 610, QH426-470, anzsrc-for: 1103 Clinical Sciences, 3105 Genetics, Loss-of-function, Fragile X Mental Retardation Protein, Genetic, Meta-Analysis as Topic, Models, Recurrence, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Rare variation, Polymorphism, anzsrc-for: 31 Biological Sciences, Autism spectrum disorder, Pediatric, Fragile X Messenger Ribonucleoprotein 1, Polymorphism, Genetic, Models, Genetic, Research, Human Genome, R, Genomics, Brain Disorders, Gene candidate score, Meta-analysis, anzsrc-for: 3105 Genetics, Common variation, Mental Health, Effect sizes, Neurological, Mutation, Medicine, Female, Functional enrichment, 31 Biological Sciences
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