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Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.

ABSTRACT: Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ?9 m '1000 Genomes Reference Panel' imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (P(Male) = 2 × 10(-49), Beta: ?0.9 SDs per allele), rs8112524 (P(Male) = 3 × 10(-8), Beta: ?0.25)] and low-frequency variants [rs2385821 (P(Male) = 6 × 10(-31), Beta: ?1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (P(Het) 0.0003-6.3 × 10(-12)), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.

SUBMITTER: Perry JR

PROVIDER: S-EPMC4706112 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.

Perry John R B JR McMahon George G Day Felix R FR Ring Susan M SM Nelson Scott M SM Lawlor Debbie A DA

Human molecular genetics 20151124 2

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m '1000 Genomes Reference Panel' imputed genetic v ...[more]

PMID: 26604150

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Project description:Abstract Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, is diagnosed based on three criteria, including a polycystic ovarian morphology (PCOM). Although the etiology of PCOS is not fully understood, a genetic component has been demonstrated. Women with PCOS have elevated serum Anti-Müllerian Hormone (AMH) levels, a hormone known to reflect the ovarian reserve. Furthermore, the AMH production per follicle is suggested to be higher in PCOS patients and this combined implies an aberrant regulation of ovarian AMH expression. Currently, some transcription factors, such as FOXL2 and SF1, have been demonstrated to play a role in the ovarian regulation of AMH promoter activity. However, still little is known about AMH gene regulation, particularly in women with PCOS. Hence, the aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in the AMH promoter on serum AMH levels in a cohort of PCOS patients. A candidate gene association study was conducted. All two-allelic SNPs located in or nearby the AMH promoter (Chr19:2,245,353 – 2,250,827bp) with a minor allele frequency > 1% and an imputation quality r2 threshold above 0.75 were included. We included Caucasian PCOS women, diagnosed based on the Rotterdam criteria. AMH levels were measured with the picoAMH assay (Ansh Labs®, Houston, Texas, USA). The association between SNPs and serum AMH levels was assessed by linear regression with Wald test of significance, allele carrier model analysis with one-way analysis of covariance (ANCOVA). All statistical models were adjusted for age, BMI and total follicle count (TFC). AMH levels were natural log transformed to obtain a normal distribution. A p-value below 8.51e-03 was considered as statistically significant, based on Matrix Spectral Decomposition with an effective number of independent variables (VeffLi) of 6. All analyses were performed using R studio. We assessed 11 SNPs in 700 Caucasian PCOS women. Human AMH promoter polymorphism rs10406324 (-220 A/G) was associated with serum levels of AMH in the linear regression analysis (β = 0.52, p=6.08e-07). This association was also present in the dominant carrier model (AA: 9.85 ng/ml ± 0.27 (n=645) vs AG/GG: 7.60ng/ml ± 0.84 (n=54/n=1), p=6.48e-05, F = 16.2). The association of TFC and the polymorphism rs10406324, corrected for Age, BMI and AMH, showed an inverse trend compared to serum AMH levels (β=-8.00, p=3.75e-03), however this result was not significant in the carrier model (AA: 42.2 ± 0.88 (n=645) vs AG/GG: 43.6 ± 2.41 (n=54/n=1), p=0.60, F = 0.281). Moreover, this SNP was not in LD with any other SNP in the selected region. The human AMH promoter polymorphism rs10406324 is associated with serum AMH levels in Caucasian PCOS women. Replication and functional analyses are necessary to further elucidate the mechanisms by which this SNP affects the AMH promoter activity.

Project description:Study questionWhat is the correlation of serum anti-Müllerian hormone (AMH) levels between two frequently used laboratory assays?Summary answerA considerable difference was found in serum AMH levels measured with the two different assays, particularly for low AMH values.What is known alreadyAMH is regarded as being a robust, highly sensitive and specific biomarker for ovarian response and has become widely used as the basis for fertility treatment decisions. However, several available assays with different reference values, in addition to inter-laboratory variations and issues of sample stability, make interpretation of the AMH values and their clinical implications complicated.Study design size durationAn observational study was performed including 269 serum samples from infertile women, originating from a RCT conducted in 2013-2016 (www.clinicaltrials.gov NCT02013973).Participants/materials setting methodSerum AMH levels analysed with the Modified Beckman Coulter Gen II ELISA assay (Premix method) were compared to AMH levels analysed with the Beckman Coulter Gen II ELISA original assay (Gen II original). All samples were handled identically and analysed with the two assays in a parallel setting.Main results and the role of chanceThe slope of the regression line showed a mean of 18% higher values with the Premix method compared to the Gen II original assay, and more than 40% higher values for AMH levels in the lower range.Limitations reasons for cautionThe Gen II original assay is no longer in clinical use as it has been replaced by the Premix method, which, in turn, recently has been further developed into an automated method.Wider implications of the findingsThe finding of differences in AMH levels between assays is clinically important and may imply an incorrect classification in the assessment of ovarian reserve. The robustness of serum AMH as a marker for ovarian reserve and as a tool for fertility counselling has to be investigated further. There is an urgent need for international standards on interpretation of AMH values for different assays.Study funding/competing interestsFinancial support was received through Sahlgrenska University Hospital (ALFGBG-70940) and the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

Dataset Information

Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.

Publications

Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.

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