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GWAS of Age at Menarche and Age at Natural Menopause

2nd International Conference on Endocrinology Oct 20-22, 2014 Chicago. GWAS of Age at Menarche and Age at Natural Menopause. Chunyan He, Sc.D. Assistant Professor Department of Epidemiology Richard M. Fairbanks School of Public Health Melvin and Bren Simon Cancer Center

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GWAS of Age at Menarche and Age at Natural Menopause

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  1. 2nd International Conference on Endocrinology Oct 20-22, 2014 Chicago GWAS of Age at Menarche and Age at Natural Menopause Chunyan He, Sc.D. Assistant Professor Department of Epidemiology Richard M. Fairbanks School of Public Health Melvin and Bren Simon Cancer Center Indiana University

  2. Outline • Why do we study menarche and natural menopause timing? • How do we identify their genetic determinants? • Candidate gene association studies • Genome-wide association studies (GWAS) • What do we learn from the GWAS findings? • How do we translate the GWAS findings? • What ‘s next?

  3. Why are We Interested? • Menarche and menopause signal the beginning and the end of normal reproductive life • Timing of two events varies between individuals • Associated with several chronic diseases and conditions • Breast cancer • Endometrial cancer • Cardiovascular diseases • Osteoporosis • Obesity and Type 2 diabetes

  4. What factors influence the timing? • Environmental factors • Obesity and BMI • Smoking • Genetic factors • Both traits are strongly correlated between mothers and daughters • High heritability estimated from family and twin studies • Age at menarche: 53-74% • Age at natural menopause: 44-65%

  5. How to identify genetic determinants ? Genetic Variants Genome-wide Association Study (GWAS) Candidate Gene Association Study Age at menarche Age at natural menopause

  6. Candidate Gene vs. GWAS Approach Candidate gene association studies exon1 exon2 intron2 promoter intron1 exon3 Phenotype Genotype gene 5’ 3’ Age at menarche Age at natural menopause DNA Genome-wide association studies (GWAS)

  7. Candidate Gene Association Studies • Genes involved in estrogen biosynthesis and metabolism pathway • ESR1 and ESR2 • CYP family genes: CYP1B1, CYP19A1 • Genes involved in vascular pathway • F5, APOE, NOS3 • Genes involved in other pathway • IGF1, CCR3, AMHR2, HDC, VDR, IL-1RA • Results were inconsistent

  8. A comprehensive candidate gene association study 38 24 49 32 36 19 13 18 49 Total 278 genes, total 18,862 SNPs He et al. Hum Genet, 2010

  9. Gene Level Test Age at Natural Menopause (16/259) Age at Menarche (9/198) He et al. Hum Genet, 2010

  10. Pathway/Group Level Test Genes that lead to the extremes of the traits also influence normal phenotypic variation in the general population He et al. Hum Genet, 2010

  11. GWAS • Require no apriori information about causal gene location and function • An unbiased yet comprehensive approach • Detect common genetic variants with moderate effect • Study chronic diseases and complex traits

  12. Our GWAS Study Design • Two independent GWAS • Nurses’ Health Study (NHS) • 2,287 women, Illumina HumanHap550 • Women’s Genome Health Study (WGHS) • 15,151 women, Illumina HumanHap300 • Joint-analysis • Total 17,438 women • 317,759 common SNPs with MAF>1% in both studies He C et al, Nat Genet, 2009

  13. Manhattan Plots: Age at Menarche He C et al, Nat Genet, 2009

  14. Loci for age at menarche 66q21 69q31.2

  15. Manhattan Plots: Age at Natural Menopause

  16. Loci for age at natural menopause

  17. Nat. Genet. May 2009

  18. Sample Size is Key for Success GWAS Consortium !!!! • Is the sample size large enough ? • Studies designed to find common variants of modest to high risk • Detecting small effects requires large sample sizes • Combine data across available GWAS to boost sample size

  19. The ReproGen Consortium The ReproGen consortium is an international network of investigators interested in better understanding the genetic basis of reproductive aging mainly among women of European ancestry. Initially included approximately 30 studies and was later expanded to more than 50 studies from the United States, Europe and Australia and from more than 100 institutions. http://www.reprogen.org/

  20. http://www.reprogen.org/

  21. The ReproGen Consortium Meta-analysis 1: Age at Menarche Meta-analysis of 32 GWAS in 87,802 women of European ancestry; replication in up to 14,731 women Confirmed the 2 previously known loci, and identified 30 new and 10 possible loci Elks et al, Nat Genet, 2010

  22. Major Findings Meta-analysis 1: Age at Menarche • Variance in age at menarche explained by the 42 known loci: 1.31% • Overlapping heritability of body size and menarche timing • included four genetic loci previously linked to body mass index (BMI) in or near the FTO, SEC16B, TRA2B, and TMEM18 genes. • Loci implicate genes involved in energy balance (BSX, CRTC1, MCHR2) and hormone regulation (INHBA, PCSK2, RXRG). • The timing of puberty is related to fatty acid metabolic pathways. Elks et al, Nat Genet, 2010

  23. The ReproGen Consortium Meta-analysis 2: Age at Menarche Meta-analysis of 57 GWAS in 132,989 women of European ancestry; replication in up to 49,427 women Identified total 106 genetic loci (explain 2.71% menarche variation) , and confirmed 41/42 previously known loci. Perry et al, Nature, 2014

  24. Major Findings Meta-analysis 2: Age at Menarche 90/106 menarche loci showed consistent directions of association with Tanner stage in boys and girls Menarche signals overlapped with reported GWAS loci for other traits: BMI, adult height, birth weight, various immunity or inflammation-related traits, breast cancer and bone mineral density Menarche signals were enriched in imprinted regions, with loci demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated novel mechanisms that regulate pubertal timing, including nuclear hormone receptors, particularly retinoic acid and GABAB receptor signalling Perry et al, Nature, 2014

  25. The ReproGen Consortium Meta-analysis: Age at Natural Menopause Meta-analysis of 22 GWAS in 38,968 women of European ancestry; replication in up to 14,435 women Confirmed the 4 previously loci, and identified 13 new loci Stolk, et al, Nat Genet, 2012

  26. Major Findings Meta-analysis: Age at Natural Menopause Variance in age at natural menopause explained by the 17 known loci: 2.5-4.1% Loci implicate genes involved in DNA repair and Immune functions. Pleotropic effect at GCKR locus: Kidney function, type 2 diabetes, continuous glycemic traits, serum albumin, C reactive protein, serum urate, and triglycerides NF-kB signaling and mitochondrial dysfunction were identified as biological processes related to timing of menopause Stolk, et al, Nat Genet, 2012

  27. Summary of GWAS Findings Genetic loci implicate novel mechanisms that regulate reproductive timing Pleiotropic genetic effects of shared loci between reproductive timing and other diseases Few shared loci between age at menarche and age at natural menopause

  28. Translation of GWAS Findings “Predictors of predictors” Age at Menarche Age at Natural Menopause SNPs predictors Age at Menarche Age at Natural Menopause predictors Breast Cancer ?????? Age at Menarche Age at Natural Menopause Breast Cancer SNPs “Mendelian Randomization”

  29. Singe- SNP Tests Test 19 menarche SNPs and 17 menopause SNPs He et al. Breast Cancer Res. 2012

  30. Genetic Risk Score (GRS) Tests He et al. Breast Cancer Res. 2012

  31. ER Status: Single-SNP Tests He et al. Breast Cancer Res. 2012

  32. ER Status: GRS Tests

  33. What’s next ? • Missing heritability • Gene-gene interactions • Gene-environment interactions • Causal variants • Other ethnic populations • African Americans, Hispanic, Asian • Functional characterization of GWAS hits • Functional consequences of variation at the identified loci • The underlying molecular mechanism • Use of genome annotation ? more variants ? rare variants ? GxG, GXE

  34. IU Richard M. Fairbanks School of Public Health Erin Wagner Jiali Han HSPH and NHS David Hunter Frank Fu Sue Hankinson Peter Kraft WGHS Daniel Chasman Julie Buring Paul Ridker Guillaume Paré NCI Stephen Chanock The ReproGen Consortium John Perry Lisette Stolk Anna Murray Kathryn Lunetta Ellen Demerath Andre Uitterlinden Joanne Murabito IUSM and IUSCC Harikrishna Nakshatri Kathy Miller Bryan Schneider Kenneth Nephew Yunlong Liu Anna Maria Storniolo Jill Henry Acknowledgments Funding The Indiana CTSI V-Foundation for Cancer Research EA-Illumina GWAS Grant

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