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      Identification of common genetic risk variants for autism spectrum disorder

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,   , , , , , , , , , , , , , , , , ,   , Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team
      Nature Genetics
      Springer Science and Business Media LLC
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <p class="first" id="d5664966e1351">Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD. </p>

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          Most cited references48

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          Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

          Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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            The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

            Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.
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              Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

              Despite strong evidence supporting the heritability of Major Depressive Disorder, previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-reported data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 reporting no history of depression through 23andMe, and meta-analyzed these results with published MDD GWAS results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with pval<1.0×10−5 in the meta-analysis were further analyzed in a replication dataset (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint-analysis over all three datasets. Some of these loci were also implicated in GWAS of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to traditional means of ascertainment for neuropsychiatric disease genomics.
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                Journal
                Nature Genetics
                Nat Genet
                Springer Science and Business Media LLC
                1061-4036
                1546-1718
                March 2019
                February 25 2019
                March 2019
                : 51
                : 3
                : 431-444
                Article
                10.1038/s41588-019-0344-8
                6454898
                30804558
                15b51bb7-ef42-4069-a441-e5a7a475109d
                © 2019

                http://www.springer.com/tdm

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