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Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

ABSTRACT: Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N = 14,877) using cognitive traits derived from the stop-signal task, namely - go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.

SUBMITTER: Arnatkeviciute A

PROVIDER: S-EPMC10827666 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

Arnatkeviciute Aurina A Lemire Mathieu M Morrison Claire C Mooney Michael M Ryabinin Peter P Roslin Nicole M NM Nikolas Molly M Coxon James J Tiego Jeggan J Hawi Ziarih Z Fornito Alex A Henrik Walter W Martinot Jean-Luc JL Martinot Marie-Laure Paillère MP Artiges Eric E Garavan Hugh H Nigg Joel J Friedman Naomi P NP Burton Christie C Schachar Russell R Crosbie Jennifer J Bellgrove Mark A MA

Molecular psychiatry 20230727 10

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining ...[more]

PMID: 37500827

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Project description:BackgroundOver 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations.MethodsTo identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis.ResultsWe identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10-11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia.ConclusionsOur study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

Dataset Information

Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

Publications

Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

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