Abstract
Lean body mass (LBM) and age at menarche (AAM) are two important complex traits for human health. The aim of this study was to identify pleiotropic genes for both traits using a powerful bivariate genome-wide association study (GWAS). Two studies, a discovery study and a replication study, were performed. In the discovery study, 909622 single nucleotide polymorphisms (SNPs) were genotyped in 801 unrelated female Han Chinese subjects using the Affymetrix human genome-wide SNP array 6.0 platform. Then, a bivariate GWAS was performed to identify the SNPs that may be important for LBM and AAM. In the replication study, significant findings from the discovery study were validated in 1692 unrelated Caucasian female subjects. One SNP rs3027009 that was bivariately associated with left arm lean mass and AAM in the discovery samples (P=7.26×10−6) and in the replication samples (P=0.005) was identified. The SNP is located at the upstream of DARC (Duffy antigen receptor for chemokines) gene, suggesting that DARC may play an important role in regulating the metabolisms of both LBM and AAM.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Sipila S, Heikkinen E, Cheng S, et al. Endogenous hormones, muscle strength, and risk of fall-related fractures in older women. J Gerontol A Biol Sci Med Sci, 2006, 61: 92–96
Karakelides H, Nair K S. Sarcopenia of aging and its metabolic impact. Curr Top Dev Biol, 2005, 68: 123–148
Hansen R D, Raja C, Aslani A, et al. Determination of skeletal muscle and fat-free mass by nuclear and dual-energy x-ray absorptiometry methods in men and women aged 51–84 y (1–3). Am J Clin Nutr, 1999, 70: 228–233
Hsu F C, Lenchik L, Nicklas B J, et al. Heritability of body composition measured by DXA in the diabetes heart study. Obes Res, 2005, 13: 312–319
Keen-Kim D, Mathews C A, Reus V I, et al. Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. Hum Mol Genet, 2006, 15: 3324–3328
Nguyen T V, Howard G M, Kelly P J, et al. Bone mass, lean mass, and fat mass: same genes or same environments? Am J Epidemiol, 1998, 147: 3–16
Wang X L, Deng F Y, Tan L J, et al. Bivariate whole genome linkage analyses for total body lean mass and BMD. J Bone Miner Res, 2008, 23: 447–452
Liu X G, Tan L J, Lei S F, et al. Genome-wide association and replication studies identified TRHR as an important gene for lean body mass. Am J Hum Genet, 2009, 84: 418–423
Kaaks R, Lukanova A, Kurzer M S. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev, 2002, 11: 1531–1543
Paganini-Hill A, Henderson V W. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol, 1994, 140: 256–261
Silman A J. Risk factors for Colles’ fracture in men and women: results from the European Prospective Osteoporosis Study. Osteoporos Int, 2003, 14: 213–218
Roy D K, O’Neill T W, Finn J D, et al. Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int, 2003, 14: 19–26
Yang T L, Chen X D, Guo Y, et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am J Hum Genet, 2008, 83: 663–674
Treloar S A, Martin N G. Age at menarche as a fitness trait: nonadditive genetic variance detected in a large twin sample. Am J Hum Genet, 1990, 47: 137–148
van den Berg S M, Boomsma D I. The familial clustering of age at menarche in extended twin families. Behav Genet, 2007, 37: 661–667
Anderson C A, Duffy D L, Martin N G, et al. Estimation of variance components for age at menarche in twin families. Behav Genet, 2007, 37: 668–677
Anderson C A, Zhu G, Falchi M, et al. A genome-wide linkage scan for age at menarche in three populations of European descent. J Clin Endocrinol Metab, 2008, 93: 3965–3970
Kaprio J, Rimpela A, Winter T, et al. Common genetic influences on BMI and age at menarche. Hum Biol, 1995, 67: 739–753
Long J R, Xu H, Zhao L J, et al. The oestrogen receptor alpha gene is linked and/or associated with age of menarche in different ethnic groups. J Med Genet, 2005, 42: 796–800
Stavrou I, Zois C, Chatzikyriakidou A, et al. Combined estrogen receptor alpha and estrogen receptor beta genotypes influence the age of menarche. Hum Reprod, 2006, 21: 554–557
Stavrou I, Zois C, Ioannidis J P, et al. Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche. Hum Reprod, 2002, 17: 1101–1105
Xita N, Tsatsoulis A, Stavrou I, et al. Association of SHBG gene polymorphism with menarche. Mol Hum Reprod, 2005, 11: 459–462
Zhao J, Xiong D H, Guo Y, et al. Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females. Hum Reprod, 2007, 22: 1789–1794
Yang F, Xiong D H, Guo Y, et al. The chemokine (C-C-motif) receptor 3 (CCR3) gene is linked and associated with age at menarche in Caucasian females. Hum Genet, 2007, 121: 35–42
Gorai I, Tanaka K, Inada M, et al. Estrogen-metabolizing gene polymorphisms, but not estrogen receptor-alpha gene polymorphisms, are associated with the onset of menarche in healthy postmenopausal Japanese women. J Clin Endocrinol Metab, 2003, 88: 799–803
Guo Y, Xiong D H, Yang T L, et al. Polymorphisms of estrogen-biosynthesis genes CYP17 and CYP19 may influence age at menarche: a genetic association study in Caucasian females. Hum Mol Genet, 2006, 15: 2401–2408
Lai J, Vesprini D, Chu W, et al. CYP gene polymorphisms and early menarche. Mol Genet Metab, 2001, 74: 449–457
Zhang L, Bonham A J, Li J, et al. Family-based bivariate association tests for quantitative traits. PLoS ONE, 2009, 4: e8133
Zhang L, Pei Y F, Li J, et al. Univariate/multivariate genome-wide association scans using data from families and unrelated samples. PLoS ONE, 2009, 4: e6502
Price A L, Patterson N J, Plenge R M, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet, 2006, 38: 904–909
Lange C, Silverman E K, Xu X, et al. A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics, 2003, 4: 195–206
Liu J, Pei Y, Papasian C J, et al. Bivariate association analyses for the mixture of continuous and binary traits with the use of extended generalized estimating equations. Genet Epidemiol, 2009, 33: 217–227
Pei Y F, Zhang L, Liu J, et al. Multivariate association test using haplotype trend regression. Ann Hum Genet, 2009, 73: 456–464
Liu Y Z, Pei Y F, Liu J F, et al. Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males. PLoS ONE, 2009, 4: e6827
Cutbush M, Mollison P L, Parkin D M. A new human blood group. Nature, 1950, 165: 188–189
Miller L H, Mason S J, Dvorak J A, et al. Erythrocyte receptors for (Plasmodium knowlesi) malaria: Duffy blood Group determinants. Science, 1975, 189: 561–563
Shen H, Schuster R, Stringer K F, et al., The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. FASEB J, 2006, 20: 59–64
He W, Neil S, Kulkarni H, et al. Duffy antigen receptor for chemokines mediates trans-infection of HIV-1 from red blood cells to target cells and affects HIV-AIDS susceptibility. Cell Host Microbe, 2008, 4: 52–62
Edderkaoui B, Baylink D J, Beamer W G, et al. Identification of mouse Duffy antigen receptor for chemokines (Darc) as a BMD QTL gene. Genome Res, 2007, 17: 577–585
Durpes M C, Hardy-Dessources M D, El Nemer W, et al. Activation state of alpha4beta1 integrin on sickle red blood cells is linked to the duffy antigen receptor for chemokines (DARC) expression. J Biol Chem, 2011, 286: 3057–3064
Wang J, He Q, Shao Y G, et al. Duffy antigen receptor for chemokines expression is related with ER expression in primary lesion of breast cancer. Chin J Clinic Med, 2009, 16: 631–633
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at Springerlink.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Hai, R., Zhang, L., Pei, Y. et al. Bivariate genome-wide association study suggests that the DARC gene influences lean body mass and age at menarche. Sci. China Life Sci. 55, 516–520 (2012). https://doi.org/10.1007/s11427-012-4327-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-012-4327-6