HLA allele-calling using whole-exome sequencing identifies 129 novel associations in 11 autoimmune diseases: a multi-ancestry analysis in the UK Biobank
HLA allele-calling using whole-exome sequencing identifies 129 novel associations in 11 autoimmune diseases: a multi-ancestry analysis in the UK Biobank
Abstract The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms (SNPs) do not perform well in this region. Instead, the field has adopted the assessment of the association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often based on genotyping arrays, these association studies impute HLA alleles, decreasing accuracy and thus statistical power for rare alleles and in non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 UK Biobank participants to directly call HLA alleles using the HLA- HD algorithm. We show this method is more accurate than imputing HLA alleles and harness the improved statistical power to identify 360 associations for 11 auto-immune phenotypes (at least 129 likely novel), leading to better insights into the specific coding polymorphisms that underlie these diseases. We show that HLA alleles with synonymous variants, often overlooked in HLA studies, can significantly influence these phenotypes. Lastly, we show that HLA sequencing may improve polygenic risk scores accuracy across ancestries. These findings allow better characterization of the role of the HLA region in human disease.
Butler-Laporte Guillaume、Abner Erik、Zhou Sirui、Su Chen-Yang、Willet Julian DS、M?gi Reedik、Nelis Mari、Milani Lili、Nakanishi Tomoko、Chen Yiheng、Metspalu Andres、Yoshiji Satoshi、Liang Kevin YH、Hultstr?m Michael、Ilboudo Yann、Richards J Brent、Lu Tianyuan、Hudjashov Georgi、Esko T?nu、Farjoun Joseph、Taliun Daniel、Forgetta Vincenzo、Estonian Biobank Research Team
Department of Epidemiology, Biostatistics and Occupational Health, McGill University||Lady Davis Institute, Jewish General Hospital, McGill University||Wellcome Trust Centre for Human Genetics, University of OxfordEstonian Genome Center, Institute of Genomics, University of TartuDepartment of Human Genetics, McGill UniversityLady Davis Institute, Jewish General Hospital, McGill UniversityLady Davis Institute, Jewish General Hospital, McGill UniversityEstonian Genome Center, Institute of Genomics, University of TartuEstonian Genome Center, Institute of Genomics, University of TartuEstonian Genome Center, Institute of Genomics, University of TartuLady Davis Institute, Jewish General Hospital, McGill University||Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University||Department of Human Genetics, McGill University||Research Fellow, Japan Society for the Promotion of ScienceLady Davis Institute, Jewish General Hospital, McGill UniversityEstonian Genome Center, Institute of Genomics, University of TartuLady Davis Institute, Jewish General Hospital, McGill University||Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University||Department of Human Genetics, McGill University||Research Fellow, Japan Society for the Promotion of ScienceLady Davis Institute, Jewish General Hospital, McGill UniversityDepartment of Epidemiology, Biostatistics and Occupational Health, McGill University||Lady Davis Institute, Jewish General Hospital, McGill University||Integrative Physiology, Department of Medical Cell Biology, Uppsala University||Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala UniversityLady Davis Institute, Jewish General Hospital, McGill UniversityDepartment of Epidemiology, Biostatistics and Occupational Health, McGill University||Lady Davis Institute, Jewish General Hospital, McGill University||Department of Human Genetics, McGill University||5 Prime Sciences Inc||Department of Twin Research, King?ˉs College London||Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health CentreLady Davis Institute, Jewish General Hospital, McGill University||5 Prime Sciences IncEstonian Genome Center, Institute of Genomics, University of TartuEstonian Genome Center, Institute of Genomics, University of TartuLady Davis Institute, Jewish General Hospital, McGill UniversityDepartment of Human Genetics, McGill UniversityLady Davis Institute, Jewish General Hospital, McGill University||5 Prime Sciences Inc
医学研究方法基础医学遗传学
Butler-Laporte Guillaume,Abner Erik,Zhou Sirui,Su Chen-Yang,Willet Julian DS,M?gi Reedik,Nelis Mari,Milani Lili,Nakanishi Tomoko,Chen Yiheng,Metspalu Andres,Yoshiji Satoshi,Liang Kevin YH,Hultstr?m Michael,Ilboudo Yann,Richards J Brent,Lu Tianyuan,Hudjashov Georgi,Esko T?nu,Farjoun Joseph,Taliun Daniel,Forgetta Vincenzo,Estonian Biobank Research Team.HLA allele-calling using whole-exome sequencing identifies 129 novel associations in 11 autoimmune diseases: a multi-ancestry analysis in the UK Biobank[EB/OL].(2025-03-28)[2025-06-30].https://www.medrxiv.org/content/10.1101/2023.01.15.23284570.点此复制
评论