目的:可以进行全基因组关联研究(GWAS)荟萃分析,包括大量来自芬兰北部创始人的绝经前年轻女性样本,确定循环抗苗勒管激素(AMH)水平的新遗传变异,并提供对AMH调节所涉及的不同生物学途径和组织中单核苷酸多态性富集的见解?
结论:荟萃分析确定了总共六个与P<5×10-8时的AMH水平相关的基因座,其中三个在CHEP2,BMP4和重要的EIF4renal富集系统和脑垂体作为组织富集分析中的顶部相关组织。
背景:AMH在女性的窦前和小窦期卵巢卵泡中表达,年龄特异性循环AMH水平的变化与几种健康状况有关。然而,目前尚不完全了解健康状况与AMH水平之间关联的生物学机制.以前的GWAS已经确定了与绝经前妇女AMH水平相关的基因座,在或接近MCM8,AMH,TEX41和CDCA7。
方法:我们对9668名绝经前妇女的循环AMH水平测量进行了GWAS荟萃分析。
方法:我们进行了GWAS荟萃分析,其中我们将来自前瞻性创始人人群队列(北芬兰出生队列1966,NFBC1966)的2619个AMH测量值(年龄31岁)与先前的GWAS荟萃分析相结合,该分析包括7049名绝经前妇女(年龄范围15-48岁)(N=9668)。使用自动化测定对NFBC1966AMH测量进行定量。我们注释了遗传变异,组合不同的数据层以优先考虑潜在的候选基因,描述了由GWAS信号富集的重要途径和组织,使用共定位分析确定了合理的调节作用,并利用公开可用的汇总统计数据来评估与多个性状的遗传和表型相关性。
结果:确定了三个新的全基因组显著位点。其中之一是与CHEK2中的c.1100delC完全连锁不平衡,与其他欧洲人口相比,芬兰人口中的c.1100delC富集了4倍。我们提出了一些与AMH相关的GWAS变体的合理调节作用,它们与与BMP4、TEX41和EIFBP41基因表达水平相关的GWAS信号共定位。基因集分析强调了肾脏系统血管形态发生的显着富集,组织富集分析将脑垂体列为最高关联。
方法:GWAS荟萃分析汇总统计数据可从GWAS目录下载,登录号为GCST90428625。
结论:这项研究仅包括欧洲血统的女性,基因表达数据中缺乏足够大小的相关组织数据阻碍了对生殖组织潜在调节作用的评估。
结论:我们的结果强调了创始人群体的力量增加和更大的样本量,以促进发现AMH水平变异的新性状相关变异。这有助于表征GWAS信号在不同生物学途径中的富集以及与AMH水平变化相关的合理遗传调节作用。
背景:这项工作已根据MATERMarieSklodowska-CurieGrant协议获得了欧盟“地平线2020研究与创新计划”的资助。813707和奥卢大学奖学金基金会和PaulonSäätiö基金会。(N.P.-G.),芬兰学院,SigridJusélius基金会,诺和诺德,奥卢大学,罗氏诊断(T.T.P.)。这项工作得到了爱沙尼亚研究理事会赠款1911(R.M.)的支持。J.R.根据第1号赠款协议,得到了欧盟“地平线2020研究与创新计划”的支持。874739(LongITools),824989(EUCAN-Connect),848158(早期原因),和733206(生命周期)。U.V.由爱沙尼亚研究理事会资助PRG(PRG1291)支持。NFBC1966获得了奥卢大学的财政支持。24000692,奥卢大学医院批准号24301140和ERDF欧洲区域发展基金赠款编号。539/2010A31592.T.T.P.收到了罗氏的资助,PerkinElmer,和GedeonRichter的科学演讲的酬金,Exeltis,Astellas,罗氏,Stragen,AstraZeneca,默克,MSD,套圈,多底膜,和AjatonTerveys.对于所有其他作者,没有竞争的利益。
OBJECTIVE: Can a genome-wide association study (GWAS) meta-analysis, including a large sample of young premenopausal women from a founder population from Northern Finland, identify novel genetic variants for circulating anti-Müllerian hormone (AMH) levels and provide insights into single-nucleotide polymorphism enrichment in different biological pathways and tissues involved in AMH regulation?
CONCLUSIONS: The meta-analysis identified a total of six loci associated with AMH levels at P < 5 × 10-8, three of which were novel in or near CHEK2, BMP4, and EIF4EBP1, as well as highlighted significant enrichment in renal system vasculature morphogenesis, and the pituitary gland as the top associated tissue in tissue enrichment analysis.
BACKGROUND: AMH is expressed by preantral and small antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with several health conditions. However, the biological mechanisms underlying the association between health conditions and AMH levels are not yet fully understood. Previous GWAS have identified loci associated with AMH levels in pre-menopausal women, in or near MCM8, AMH, TEX41, and CDCA7.
METHODS: We performed a GWAS meta-analysis for circulating AMH level measurements in 9668 pre-menopausal women.
METHODS: We performed a GWAS meta-analysis in which we combined 2619 AMH measurements (at age 31 years) from a prospective founder population cohort (Northern Finland Birth Cohort 1966, NFBC1966) with a previous GWAS meta-analysis that included 7049 pre-menopausal women (age range 15-48 years) (N = 9668). NFBC1966 AMH measurements were quantified using an automated assay. We annotated the genetic variants, combined different data layers to prioritize potential candidate genes, described significant pathways and tissues enriched by the GWAS signals, identified plausible regulatory roles using colocalization analysis, and leveraged publicly available summary statistics to assess genetic and phenotypic correlations with multiple traits.
RESULTS: Three novel genome-wide significant loci were identified. One of these is in complete linkage disequilibrium with c.1100delC in CHEK2, which is found to be 4-fold enriched in the Finnish population compared to other European populations. We propose a plausible regulatory effect of some of the GWAS variants linked to AMH, as they colocalize with GWAS signals associated with gene expression levels of BMP4, TEX41, and EIFBP41. Gene set analysis highlighted significant enrichment in renal system vasculature morphogenesis, and tissue enrichment analysis ranked the pituitary gland as the top association.
METHODS: The GWAS meta-analysis summary statistics are available for download from the GWAS Catalogue with accession number GCST90428625.
CONCLUSIONS: This study only included women of European ancestry and the lack of sufficiently sized relevant tissue data in gene expression datasets hinders the assessment of potential regulatory effects in reproductive tissues.
CONCLUSIONS: Our results highlight the increased power of founder populations and larger sample sizes to boost the discovery of novel trait-associated variants underlying variation in AMH levels, which aided the characterization of GWAS signals enrichment in different biological pathways and plausible genetic regulatory effects linked with AMH level variation for the first time.
BACKGROUND: This work has received funding from the European Union\'s Horizon 2020 Research and Innovation Programme under the MATER Marie Sklodowska-Curie Grant Agreement No. 813707 and Oulu University Scholarship Foundation and Paulon Säätiö Foundation. (N.P.-G.), Academy of Finland, Sigrid Jusélius Foundation, Novo Nordisk, University of Oulu, Roche Diagnostics (T.T.P.). This work was supported by the Estonian Research Council Grant 1911 (R.M.). J.R. was supported by the European Union\'s Horizon 2020 Research and Innovation Program under Grant Agreements No. 874739 (LongITools), 824989 (EUCAN-Connect), 848158 (EarlyCause), and 733206 (LifeCycle). U.V. was supported by the Estonian Research Council grant PRG (PRG1291). The NFBC1966 received financial support from University of Oulu Grant No. 24000692, Oulu University Hospital Grant No. 24301140, and ERDF European Regional Development Fund Grant No. 539/2010 A31592. T.T.P. has received grants from Roche, Perkin Elmer, and honoraria for scientific presentations from Gedeon Richter, Exeltis, Astellas, Roche, Stragen, Astra Zeneca, Merck, MSD, Ferring, Duodecim, and Ajaton Terveys. For all other authors, there are no competing interests.