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Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.

ABSTRACT: By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10-10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.

SUBMITTER: Genovese G

PROVIDER: S-EPMC5104192 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.

Genovese Giulio G Fromer Menachem M Stahl Eli A EA Ruderfer Douglas M DM Chambert Kimberly K Landén Mikael M Moran Jennifer L JL Purcell Shaun M SM Sklar Pamela P Sullivan Patrick F PF Hultman Christina M CM McCarroll Steven A SA

Nature neuroscience 20161003 11

By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10<sup>-10< ...[more]

PMID: 27694994

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Project description:In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

Project description:Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

Dataset Information

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.

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Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.

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