Dataset Information

Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia.

ABSTRACT:

Objective

Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions.

Method

Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined. Three classes of rare CNVs were assessed: CNVs previously associated with schizophrenia, CNVs with large deletions ≥500 kb, and total CNV burden. The mean polygenic risk scores (PRSs) between study subjects with and without rare CNVs were compared, and joint effects of PRS and CNVs on schizophrenia liability were modeled by using logistic regression.

Results

Schizophrenia case subjects carrying risk CNVs had a lower polygenic risk than case subjects without risk CNVs but a higher risk than control subjects. For case subjects carrying known risk CNVs, the PRS was diminished in proportion to the effect size of the CNV. The strongly associated 22q11.2 deletion required little added PRS to produce schizophrenia. Large deletions and increased CNV burden were also associated with lower polygenic risk in schizophrenia case subjects but not in control subjects or after removal of known risk CNV carriers.

Conclusions

The authors found evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia, and the results for large deletions and total CNV burden support an additive model. These findings offer insights into the genetic architecture of schizophrenia by illuminating how different established genetic risk factors act and interact to influence liability to schizophrenia.

SUBMITTER: Bergen SE

PROVIDER: S-EPMC6408268 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia.

Bergen Sarah E SE Ploner Alexander A Howrigan Daniel D O'Donovan Michael C MC Smoller Jordan W JW Sullivan Patrick F PF Sebat Jonathan J Neale Benjamin B Kendler Kenneth S KS

The American journal of psychiatry 20181105 1

<h4>Objective</h4>Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions.<h4>Method</h4>Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psy ...[more]

PMID: 30392412

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Project description:BackgroundCopy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.MethodsAssessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank.ResultsWe identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated their pathogenicity, with many associations being supported by colocalization with both common and rare single-nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacted renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Finally, we show that while the total burden of rare CNVs-and especially deletions-strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS.ConclusionsOur results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

Project description:ImportanceThe role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear.ObjectiveTo examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression.Design, setting, and participantsThis case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018.ExposuresCNV carrier status.Main outcomes and measuresFor the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression.ResultsCopy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression.Conclusions and relevanceNeurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

Dataset Information

Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia.

Objective

Method

Results

Conclusions

Publications

Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia.

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