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Genome-wide association study identifies Sjogren's risk loci with functional implications in immune and glandular cells.

ABSTRACT: Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

SUBMITTER: Khatri B

PROVIDER: S-EPMC9329286 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.

Khatri Bhuwan B Tessneer Kandice L KL Rasmussen Astrid A Aghakhanian Farhang F Reksten Tove Ragna TR Adler Adam A Alevizos Ilias I Anaya Juan-Manuel JM Aqrawi Lara A LA Baecklund Eva E Brun Johan G JG Bucher Sara Magnusson SM Eloranta Maija-Leena ML Engelke Fiona F Forsblad-d'Elia Helena H Glenn Stuart B SB Hammenfors Daniel D Imgenberg-Kreuz Juliana J Jensen Janicke Liaaen JL Johnsen Svein Joar Auglænd SJA Jonsson Malin V MV Kvarnström Marika M Kelly Jennifer A JA Li He H Mandl Thomas T Martín Javier J Nocturne Gaétane G Norheim Katrine Brække KB Palm Øyvind Ø Skarstein Kathrine K Stolarczyk Anna M AM Taylor Kimberly E KE Teruel Maria M Theander Elke E Venuturupalli Swamy S Wallace Daniel J DJ Grundahl Kiely M KM Hefner Kimberly S KS Radfar Lida L Lewis David M DM Stone Donald U DU Kaufman C Erick CE Brennan Michael T MT Guthridge Joel M JM James Judith A JA Scofield R Hal RH Gaffney Patrick M PM Criswell Lindsey A LA Jonsson Roland R Eriksson Per P Bowman Simon J SJ Omdal Roald R Rönnblom Lars L Warner Blake B Rischmueller Maureen M Witte Torsten T Farris A Darise AD Mariette Xavier X Alarcon-Riquelme Marta E ME Shiboski Caroline H CH Wahren-Herlenius Marie M Ng Wan-Fai WF Sivils Kathy L KL Adrianto Indra I Nordmark Gunnel G Lessard Christopher J CJ

Nature communications 20220727 1

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define lo ...[more]

PMID: 35896530

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Project description:Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power of population-genetic analyses for the rapid identification of genes contributing to complex traits in microbial species.

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Genome-wide association study identifies Sjogren's risk loci with functional implications in immune and glandular cells.

Publications

Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.

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