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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

ABSTRACT: Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P?=?1.50?×?10-8, OR?=?1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency?

SUBMITTER: Dand N

PROVIDER: S-EPMC5886170 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Dand Nick N Mucha Sören S Tsoi Lam C LC Mahil Satveer K SK Stuart Philip E PE Arnold Andreas A Baurecht Hansjörg H Burden A David AD Callis Duffin Kristina K Chandran Vinod V Curtis Charles J CJ Das Sayantan S Ellinghaus David D Ellinghaus Eva E Enerback Charlotta C Esko Tõnu T Gladman Dafna D DD Griffiths Christopher E M CEM Gudjonsson Johann E JE Hoffman Per P Homuth Georg G Hüffmeier Ulrike U Krueger Gerald G GG Laudes Matthias M Lee Sang Hyuck SH Lieb Wolfgang W Lim Henry W HW Löhr Sabine S Mrowietz Ulrich U Müller-Nurayid Martina M Nöthen Markus M Peters Annette A Rahman Proton P Reis André A Reis André A Reynolds Nick J NJ Rodriguez Elke E Schmidt Carsten O CO Spain Sarah L SL Strauch Konstantin K Tejasvi Trilokraj T Voorhees John J JJ Warren Richard B RB Weichenthal Michael M Weidinger Stephan S Zawistowski Matthew M Nair Rajan P RP Capon Francesca F Smith Catherine H CH Trembath Richard C RC Abecasis Goncalo R GR Elder James T JT Franke Andre A Simpson Michael A MA Barker Jonathan N JN

Human molecular genetics 20171101 21

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk l ...[more]

PMID: 28973304

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Project description:BackgroundBipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness.MethodsOverall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder-manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a genebased segregation test.ResultsWe identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies - or variants in linkage disequilibrium with those variants - did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014).LimitationsWe did not examine non-coding variants, but they may explain the remaining linkage signal.ConclusionCombining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

Dataset Information

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Publications

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Similar Datasets

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