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Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

ABSTRACT: Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes¹. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10^-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

SUBMITTER: Liu D

PROVIDER: S-EPMC10011128 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Liu Dongjing D Meyer Dara D Fennessy Brian B Feng Claudia C Cheng Esther E Johnson Jessica S JS Park You Jeong YJ Rieder Marysia-Kolbe MK Ascolillo Steven S de Pins Agathe A Dobbyn Amanda A Lebovitch Dannielle D Moya Emily E Nguyen Tan-Hoang TH Wilkins Lillian L Hassan Arsalan A Burdick Katherine E KE Buxbaum Joseph D JD Domenici Enrico E Frangou Sophia S Hartmann Annette M AM Laurent-Levinson Claudine C Malhotra Dheeraj D Pato Carlos N CN Pato Michele T MT Ressler Kerry K Roussos Panos P Rujescu Dan D Arango Celso C Bertolino Alessandro A Blasi Giuseppe G Bocchio-Chiavetto Luisella L Campion Dominique D Carr Vaughan V Fullerton Janice M JM Gennarelli Massimo M González-Peñas Javier J Levinson Douglas F DF Mowry Bryan B Nimgaokar Vishwajit L VL Pergola Giulio G Rampino Antonio A Cervilla Jorge A JA Rivera Margarita M Schwab Sibylle G SG Wildenauer Dieter B DB Daly Mark M Neale Benjamin B Singh Tarjinder T O'Donovan Michael C MC Owen Michael J MJ Walters James T JT Ayub Muhammad M Malhotra Anil K AK Lencz Todd T Sullivan Patrick F PF Sklar Pamela P Stahl Eli A EA Huckins Laura M LM Charney Alexander W AW

Nature genetics 20230313 3

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes<sup>1</sup>. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings ...[more]

PMID: 36914870

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Project description:Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment-test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal-activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package.

Project description:ImportanceProtein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.ObjectiveTo evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.Design, setting, and participantsThis studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.ExposuresPTVs in APOB and PCSK9.Main outcomes and measuresEstimated untreated LDL cholesterol levels and CHD.ResultsAmong 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).Conclusions and relevanceAmong 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Dataset Information

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Publications

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

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