Shared genetic factors for age at natural menopause in Iranian and European women.

STUDY QUESTION: Do differences in heritable genetic factors explain some of the difference in age at natural menopause (ANM) among populations?

SUMMARY ANSWER: One single nucleotide polymorphism (SNP)-ANM association (rs16991615) detected in European women was replicated in Iranian women.

WHAT IS KNOWN ALREADY: Genetics plays an important role in ANM, and well-powered genome-wide association studies (GWAS) of ANM performed in European women have discovered many statistically significant SNP-ANM associations. Average ANM varies by ethnicity, and population-specific differences in ANM-associated alleles may in part explain these differences.

STUDY DESIGN, SIZE, DURATION: After quality control procedures, 97 SNPs were analyzed in genotype data of 828 Iranian women who experienced natural menopause. SNP genotyping data were used to perform linear regression analyses with ANM as a quantitative trait. Study participants were drawn from the population-based Tehran Lipid and Glucose Study based in Tehran, Iran. This study was performed between February 2009 and March 2012.

PARTICIPANTS/MATERIALS, SETTING AND METHODS: Based on an ANM-GWAS literature review, eight SNPs at four loci previously associated with ANM in European women were tested for replication in Iranian women. Linear regression analyses were performed including (n = 828) and excluding (n = 783) women who experience premature ovarian failure (ANM before 40 years of age). In addition, to search for novel population-specific ANM risk alleles, a pool-based GWAS was performed using this collection of Iranian women. Two DNA pools were constructed and compared: an 'early' ANM pool (lower 20(th) percentile of menopause ages, 40-45 years, n = 165) and a 'late' ANM pool (upper 20(th) percentile of menopause ages, 54-65 years, n = 187). Each DNA pool was assayed on four Illumina Human1M-Duo arrays, and allele-based tests of association were used to rank SNPs. One hundred and two highly ranked SNPs were chosen for individual genotyping by Sequenom MassARRAY and association analysis in the Iranian women.

MAIN RESULTS AND THE ROLE OF CHANCE: One SNP-ANM association previously detected in European women was replicated in Iranian women (rs16991615; β = 1.07, standard error (SE): 0.49, P = 0.02). SNPs at the previously reported 19q13.42 and 6p24.2 loci also approached statistical significance and had consistent SNP effects (magnitude and direction) in Iranian women (rs1172822; β = -0.39, SE: 0.22, P = 0.08; and rs2153157, β = 0.41, SE: 0.21, P = 0.05). We found little evidence for novel SNP-ANM associations in Iranian women; no SNP selected based on the pool-based GWAS achieved genome-wide significance.

LIMITATIONS, REASONS FOR CAUTION: Due to small sample size this study was powered to reliably detect only moderate-to-large SNP effect sizes. This limited our ability to replicate many of the previously reported SNP-ANM risk alleles and to discover novel SNP-ANM associations' specific to the Iranian population. In performing our pool-based GWAS, a reduction in power was introduced relative to a conventional GWAS.

WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that European and Iranian women share ANM-associated genetic variants. Our study was underpowered but for all SNPs tested the direction of the effect was consistent with data from the European study. Therefore, we anticipate that many (if not all) of the ANM-associated SNPs discovered in European women will replicate in Iranian women upon genotyping a sufficient number of women. Our data do not support the hypothesis that population-specific SNP-ANM associations explain population-specific differences in the mean ANM.