Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.,American Journal of Human Genetics

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Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-12-26 , DOI: 10.1016/j.ajhg.2019.12.002
Laura M Raffield ₁ , Apoorva K Iyengar ₁ , Biqi Wang ₂ , Sheila M Gaynor ₃ , Cassandra N Spracklen ₁ , Xue Zhong ₄ , Madeline H Kowalski ₅ , Shabnam Salimi ₆ , Linda M Polfus ₇ , Emelia J Benjamin ₈ , Joshua C Bis ₉ , Russell Bowler ₁₀ , Brian E Cade ₁₁ , Won Jung Choi ₁₂ , Alejandro P Comellas ₁₃ , Adolfo Correa ₁₄ , Pedro Cruz ₁₅ , Harsha Doddapaneni ₁₆ , Peter Durda ₁₇ , Stephanie M Gogarten ₁₈ , Deepti Jain ₁₈ , Ryan W Kim ₁₂ , Brian G Kral ₁₉ , Leslie A Lange ₂₀ , Martin G Larson ₂₁ , Cecelia Laurie ₁₈ , Jiwon Lee ₂₂ , Seonwook Lee ₁₂ , Joshua P Lewis ₂₃ , Ginger A Metcalf ₁₆ , Braxton D Mitchell ₂₄ , Zeineen Momin ₁₆ , Donna M Muzny ₁₆ , Nathan Pankratz ₂₅ , Cheol Joo Park ₁₂ , Stephen S Rich ₂₆ , Jerome I Rotter ₂₇ , Kathleen Ryan ₂₃ , Daekwan Seo ₁₂ , Russell P Tracy ₂₈ , Karine A Viaud-Martinez ₁₅ , Lisa R Yanek ₂₉ , Lue Ping Zhao ₃₀ , Xihong Lin ₃₁ , Bingshan Li ₃₂ , Yun Li ₃₃ , Josée Dupuis ₂₁ , Alexander P Reiner ₃₄ , Karen L Mohlke ₁ , Paul L Auer ₃₅ , ,

Affiliation

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA 90089, USA.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA.
Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98101, USA.
Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, National Jewish Health, Denver, CO 80206, USA.
Department of Medicine, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
Macrogen USA, Rockville, MD 20850, USA.
Department of Medicine, Division of Pulmonary and Critical Care, University of Iowa, Iowa City, IA 52242, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Illumina Laboratory Services, Illumina Inc., San Diego, CA 92122, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05446, USA.
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA.
Department of Medicine, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05446, USA; Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT 05446, USA.
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Washington, Seattle, WA 98195, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Joseph J. Zilber School of Public Health, University of Wisconsin Milwaukee, Milwaukee, WI 53205, USA.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

中文翻译：

通过多祖先队列中的全基因组测序鉴定 CRP 位点的等位基因异质性。

全基因组测序 (WGS) 可以改善对低频和罕见变异的评估，特别是在现有基因组研究中代表性不足的非欧洲人群中。 C 反应蛋白 (CRP) 是慢性炎症的生物标志物，其遗传决定因素已得到广泛研究，现有的全基因组关联研究 (GWAS) 在 >200,000 欧洲血统个体中进行。为了发现与 CRP 水平相关的新位点，我们利用精准医学跨组学 (TOPMed) 计划的全基因组测序（~38×覆盖率）检查了多祖先群体（n = 23,279）。我们发现了 CRP 位点上八个不同关联的证据，包括以前未发现的两个变体（rs11265259 和 rs181704186），这两个变体都是非编码的，并且在非洲血统的个体中更常见（∼10% 和∼1%）在东亚、南亚和欧洲血统的 1000 个基因组群体中，分别存在次要等位基因频率和稀有或单态性）。我们表明，rs181704186 的次要 (G) 等位基因与体外 CRP 水平降低、转录活性和蛋白质结合降低相关，为这种非洲血统特异性信号提供了一个合理的分子机制。 rs181704186-G 纯合个体的平均 CRP 水平为 0.23 mg/L，而 rs181704186 杂合个体的平均 CRP 为 2.97 mg/L，主要等位基因纯合子的平均 CRP 为 4.11 mg/L。这项研究证明了全基因组测序在多种族人群中的实用性，可推动发现具有重大影响的复杂性状关联，并识别非编码调控区域的功能等位基因。

更新日期：2019-12-27

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