Year: 2024
Type: article
Study design: Observational Study
Abstract: Understanding the genetic basis of blood tests routinely acquired in clinical care can provide insights into several aspects of human physiology and disease. Previous efforts have almost exclusively focussed on individuals of European descent, severely limiting generalizability to ancestrally-diverse populations. Here we describe the largest genome-wide association study of quantitative traits in a cohort of South Asian ancestry. We tested the association of >7 million autosomal, common (minor allele frequency [MAF] > 1%) Single Nucleotide Polymorphisms (SNPs) genotyped using the Illumina Global Screening Array version 3 and imputed from the TOPMED-r2 panel. We defined 39 quantitative blood test traits from Electronic Healthcare Records (EHRs) – both primary care and hospital records - of ~40,000 British Bangladeshi and British Pakistani adults. We discover eight novel locus-trait associations which were specific to Genes & Health, including CUX2 (serum vitamin D), BRD3OS (glycated haemoglobin) and STMN2 (lymphocyte count). By performing multi-ancestry meta-analysis and fine mapping using data from UK Biobank, we demonstrate ancestry-specific causal variants within the PIEZO1 and HBB loci which were associated with alterations in red cell traits and glycated haemoglobin. The South Asian ancestry-specific causal signal for glycated haemoglobin, rs563555492(MAF 3.2% in 1,000 Genomes South Asian ancestry samples), is a missense variant in PIEZO1 which is monomorphic in other ancestries, and illustrates how ancestry-specific genetic variants may be of relevance for the design of clinical reference ranges. Our results shed light on the genetic basis of clinically-relevant quantitative traits in an under-represented population, and emphasise the importance of ancestral diversity in genetic studies.
Source: Nature Communications
Authors: Benjamin M. Jacobs, Daniel Stow, Sam Hodgson, Julia Zöllner, Miriam Samuel, Stavroula Kanoni, Saeed Bidi, Shaheen Akhtar, Mohammad Anwar, Elena Arciero, Omar Asgar, Samina Ashraf, Saeed Bidi, Gerome Breen, James Broster, Raymond Chung, David Collier, Charles J. Curtis, Shabana Chaudhary, Megan Clinch, Grainne Colligan, Panos Deloukas, Ceri Durham, Faiza Durrani, Fabiola Eto, Sarah Finer, Joseph Gafton, Ana Angel Garcia, Chris Griffiths, Joanne Harvey, Teng Heng, Sam Hodgson, Qin Qin Huang, Matt Hurles, Karen A. Hunt, Shapna Hussain, Kamrul Islam, Vivek Iyer, Ben Jacobs, Ahsan Khan, Cath Lavery, Sang Hyuck Lee, Robin Lerner, Daniel MacArthur, Daniel Malawsky, Hilary Martin, Dan Mason, Rohini Mathur, Mohammed Bodrul Mazid, John McDermott, Caroline Morton, Bill Newman, Elizabeth Owor, Asma Qureshi, Samiha Rahman, Shwetha Ramachandrappa, Mehru Reza, Jessry Russell, Nishat Safa, Miriam Samuel, Michael Simpson, John Solly, Marie Spreckley, Daniel Stow, Michael Taylor, Richard C. Trembath, Karen Tricker, Nasir Uddin, David A. van Heel, Klaudia Walter, Caroline Winckley, Suzanne Wood, John Wright, Julia Zollner, Klaudia Walter, Claudia Langenberg, Ruth Dobson, Sarah Finer, Caroline Morton, Moneeza K. Siddiqui, Hilary C. Martin, Maik Pietzner, Rohini Mathur, David A. van Heel
Institutions: Queen Mary University of London, Barts Health NHS Trust, Royal London Hospital, University College London, William Harvey Research Institute, Wellcome Sanger Institute, Manchester University NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, King's College London, Blizard Institute, Garvan Institute of Medical Research, University of Manchester, Bradford Institute for Health Research, Berlin Institute of Health at Charité - Universitätsmedizin Berlin
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Alnylam Pharmaceuticals, Aims2Cure, Wellcome Trust, Broad Institute, Barts Charity, Maze Therapeutics, National Institute for Health and Care Research, Multiple Sclerosis Society, King's College London, Public Health England, Novo Nordisk, Barts Health NHS Trust, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Health Data Research UK
Awards: G1412811091, Understanding physical/mental health multimorbidity in underrepresented populations, G2164313650, G2457841196, East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians, Is exposure to toxic metals contributing to ethnic and social health inequalities in children and young adults in the UK?, G3417935152, G3578122227, Genomic determinants of Multiple Sclerosis susceptibility in an ethnically diverse population, G4912392683, G5575271627, Genes & Health Longitudinal Population Study, Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative (LINC))., G829604083, G942680792
OpenAlex ID: W4403445809