A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

被引：134

作者：

Coviello, Andrea D. ^{[1
,2
,3
]}

Haring, Robin ^{[4
]}

Wellons, Melissa ^{[5
,6
]}

Vaidya, Dhananjay ^{[7
]}

Lehtimaki, Terho ^{[8
,9
]}

Keildson, Sarah ^{[10
]}

Lunetta, Kathryn L. ^{[11
]}

He, Chunyan ^{[12
,13
]}

Fornage, Myriam ^{[14
]}

Lagou, Vasiliki ^{[10
,15
]}

Mangino, Massimo

Onland-Moret, N. Charlotte ^{[17
]}

Chen, Brian ^{[18
,19
]}

Eriksson, Joel ^{[20
]}

Garcia, Melissa ^{[21
]}

Mei, Yong ^{[22
,23
]}

Koster, Annemarie ^{[21
]}

Lohman, Kurt ^{[22
]}

Lyytikainen, Leo-Pekka

Petersen, Ann-Kristin ^{[24
]}

Prescott, Jennifer ^{[25
,26
,27
]}

Stolk, Lisette ^{[28
,29
]}

Vandenput, Liesbeth ^{[20
]}

Wood, Andrew R. ^{[30
]}

Zhuang, Wei Vivian ^{[11
]}

Ruokonen, Aimo ^{[31
]}

Hartikainen, Anna-Liisa ^{[32
]}

Pouta, Anneli ^{[33
,34
]}

Bandinelli, Stefania ^{[35
]}

Biffar, Reiner ^{[36
]}

Brabant, Georg ^{[37
]}

Cox, David G. ^{[38
,39
]}

Chen, Yuhui ^{[10
]}

Cummings, Steven ^{[40
]}

Ferrucci, Luigi ^{[41
]}

Gunter, Marc J. ^{[39
]}

Hankinson, Susan E. ^{[26
,27
,42
]}

Martikainen, Hannu

Hofman, Albert ^{[29
,43
]}

Homuth, Georg ^{[44
]}

Illig, Thomas ^{[45
,46
]}

Jansson, John-Olov ^{[20
]}

Johnson, Andrew D.

Karasik, David ^{[27
,47
]}

Karlsson, Magnus ^{[48
,49
]}

Kettunen, Johannes ^{[50
,51
]}

Kiel, Douglas P. ^{[27
,47
]}

Kraft, Peter ^{[52
]}

Liu, Jingmin ^{[53
]}

Ljunggren, Osten ^{[54
]}

机构：

[1] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA

[2] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA

[3] Natl Heart Lng & Blood Inst Framingham Heart Stud, Framingham, MA USA

[4] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Univ Med, Greifswald, Germany

[5] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[6] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA

[7] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[8] Tampere Univ Hosp, Fimlab Labs, Dept Clin Chem, Tampere, Finland

[9] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland

[10] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[11] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[12] Indiana Univ Sch Med, Dept Publ Hlth, Indianapolis, IN USA

[13] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA

[14] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA

[15] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[16] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[17] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[18] Univ Calif Los Angeles, Program Genom & Nutr, Los Angeles, CA USA

[19] Univ Calif Los Angeles, Ctr Metab Dis Prevent, Sch Publ Hlth, Los Angeles, CA USA

[20] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden

[21] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[22] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA

[23] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA

[24] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[25] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[26] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

[27] Harvard Univ, Sch Med, Boston, MA USA

[28] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[29] Netherlands Consortium Healthy Aging, Rotterdam, Netherlands

[30] Univ Exeter, Peninsula Med Sch, Exeter, Devon, England

[31] Univ Oulu, Inst Diagnost, Oulu, Finland

[32] Univ Hosp Oulu, Dept Obstet & Gynecol, Oulu, Finland

[33] Univ Oulu, Natl Inst Hlth & Welf, Oulu, Finland

[34] Univ Oulu, Inst Hlth Sci, Oulu, Finland

[35] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy

[36] Ernst Moritz Arndt Univ Greifswald, Dept Prosthet Dent Gerostomatol & Dent Mat, Greifswald, Germany

[37] Med Univ Lubeck, D-23538 Lubeck, Germany

[38] INSERM, U1052, Canc Res Ctr Lyon, F-69008 Lyon, France

[39] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[40] Calif Pacific Med Ctr, San Francisco, CA USA

[41] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA

[42] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA

[43] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[44] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[45] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[46] Hannover Med Sch, Hannover Unified Biobank, D-3000 Hannover, Germany

[47] Hebrew SeniorLife Inst Aging Res, Boston, MA USA

[48] Lund Univ, Clin Mol Osteoporosis Res Unit, Dept Clin Sci, Malmo, Sweden

[49] Lund Univ, Dept Orthopaed, Malmo, Sweden

[50] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

来源：

PLOS GENETICS | 2012年 / 8卷 / 07期

基金：

美国国家卫生研究院; 芬兰科学院; 英国医学研究理事会; 英国惠康基金; 瑞典研究理事会; 美国国家科学基金会; 英国生物技术与生命科学研究理事会;

关键词：

POLYCYSTIC-OVARY-SYNDROME; RECEPTOR TYROSINE KINASE; INSULIN-RECEPTOR; SHBG GENE; MEDICAL PROGRESS; GCKR RS780094; RISK; POLYMORPHISM; EXPRESSION; UGT2B17;

D O I：

10.1371/journal.pgen.1002805

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

引用

页数：12

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