Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study

被引：60

作者：

Carty, C. L. ^{[1
]}

Spencer, K. L. ^{[2
]}

Setiawan, V. W. ^{[3
]}

Fernandez-Rhodes, L. ^{[4
]}

Malinowski, J. ^{[5
]}

Buyske, S. ^{[6
,7
]}

Young, A. ^{[1
]}

Jorgensen, N. W. ^{[8
]}

Cheng, I. ^{[9
]}

Carlson, C. S. ^{[1
]}

Brown-Gentry, K. ^{[5
]}

Goodloe, R. ^{[5
]}

Park, A. ^{[10
]}

Parikh, N. I. ^{[11
,12
]}

Henderson, B. ^{[3
]}

Le Marchand, L. ^{[13
]}

Wactawski-Wende, J. ^{[14
]}

Fornage, M. ^{[15
]}

Matise, T. C. ^{[6
]}

Hindorff, L. A. ^{[16
]}

Arnold, A. M. ^{[8
]}

Haiman, C. A. ^{[3
]}

Franceschini, N. ^{[4
]}

Peters, U. ^{[1
]}

Crawford, D. C. ^{[5
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[2] Heidelberg Univ, Tiffin, OH USA

[3] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[4] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[5] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA

[6] Rutgers State Univ, Dept Genet, Piscataway, NJ USA

[7] Rutgers State Univ, Dept Stat, Piscataway, NJ USA

[8] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[9] Canc Prevent Inst Calif, Fremont, CA USA

[10] Georgetown Univ, Sch Med, Dept Obstet & Gynecol, Washington Hosp Ctr, Washington, DC 20007 USA

[11] Univ Hawaii, John A Burns Sch Med, Queens Med Ctr, Honolulu, HI 96822 USA

[12] Univ Hawaii, Div Cardiovasc, Queens Med Ctr, Honolulu, HI 96822 USA

[13] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA

[14] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA

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

[16] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA

来源：

HUMAN REPRODUCTION | 2013年 / 28卷 / 06期

关键词：

menopause; menarche; genome-wide association study; race; ethnicity; single nucleotide polymorphism; NATURAL MENOPAUSE; WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; SEQUENCE VARIANTS; AMERICAN-INDIANS; US GIRLS; RISK; METAANALYSIS; REPRODUCIBILITY; DETERMINANTS;

D O I：

10.1093/humrep/det071

中图分类号：

R71 [妇产科学];

学科分类号：

100211 ;

摘要：

Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. SNPs previously associated with ANM (n 5 SNPs) and AM (n 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P 0.01 for ANM analyses and P 0.017 for AM analyses. We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest.

引用

页码：1695 / 1706

页数：12

共 68 条

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