Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

By A. Pardiñas, P. Holmans, A. Pocklington, V. Escott-Price, S. Ripke, N. Carrera, S. Legge, Sophie Bishop, Darren Cameron, M. Hamshere and 137 more. Nature Genetics, 2018

1,432 citations recorded by the source corpus.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population. A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/3ea878a99295dc60bf2f5920cc4470952a98c17e

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Citations in the corpus

Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022, background): “These include SLC39A8 in which rs13107325, previously a moderately high credible SNP 23 , is now strongly supported as causal (PP > 0.99).”
Comparative genetic architectures of schizophrenia in East Asian and European populations (2018, neutral): “2,3,7,8 ).”
Integrative functional genomic analysis of human brain development and neuropsychiatric risks (2018, methodology): “Toward this end, we collected GWAS data concerning neuropsychiatric disorders or personality traits including schizophrenia (SCZ) from CLOZUK (37), Alzheimer’s disease (AD) from IGAP (38), Parkinson’s disease (PD) (39), autism spectrum disorder (ASD) (40), attention deficit hyperactivity disorder (A”
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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “GWAS results from SCZ (59), BD (97), and ASD (38), using stratified LD score regression (*FDR < 0.”
Comparative genetic architectures of schizophrenia in East Asian and European populations. (2019, background): “org/ricopili/home) with the following steps and parameters: (1) excluding variants with call rate below 95%; (2) excluding subjects with call rate below 98%; (3) excluding monomorphic variants; (4) excluding subjects with inbred coefficient above 0.”