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No KAIMRC Affiliation (AlTurki – KAMC).

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Whole-genome sequence-based analysis of thyroid function


Taylor, P., Porcu, E., Chew, S., Campbell, P., Traglia, M., et al.


Nature Communications

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Thyroid Research Group, Institute of Molecular & Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. ;  Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari CA 09042, Italy. ; Dipartimento di Scienze Biomediche, Universita` di Sassari, Sassari 07100, Italy. ; Center for Statistical Genetics, Biostatistics Department, University of Michigan, Ann Arbor, Michigan 48109-2029, USA. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia WA 6009, Australia. ; Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano 20132, Italy. ;  School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia WA 6009, Australia.; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol BS8 2BN, UK. ; The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, Cambridge, UK., ; Department of Pathology, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia. , et al.



Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N¼ 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAFZ1%) associated with TSH and FT4 (N¼ 16,335). For TSH, we identify a novel variant in SYN2 (MAF¼ 23.5%, P¼ 6.15 10 9) and a new independent variant in PDE8B (MAF¼ 10.4%, P¼ 5.94 10 14). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF¼ 3.2%, P¼ 1.27 10 9) tagging a rare TTR variant (MAF¼ 0.4%, P¼ 2.14 10 11). All common variants explain Z20% of the variance in TSH and FT4. Analysis of rare variants (MAFo1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.