| Background:PCOS is the most prevalent endocrine disorder affecting women of reproductive age.The etiology of PCOS is not fully understood and genetic factor are strongly involved.Previous genome-wide association study?GWAS?in Han Chinese identified 11 susceptibility loci for PCOS.A recent GWAS has identified two new susceptibility loci for PCOS in women of European ancestry.Besides,PCOS women commonly present with higher risk of dyslipidemia and they might share some similar genetic predisposition.PCOS is of higher ovary response and is the risk factor for ovarian hyperstimulation syndrome?OHSS?during IVF/ICSI treatment.Genetic factors are strongly involved in the variety of ovary response and OHSS.Objective:1)To investigate the effect of the European GWAS loci on PCOS susceptibility in Han Chinese women,and then evaluate the genetic risk score based these three GWASs.2)To investigate whether dyslipidemia-related genes are associated with PCOS.3)To investigate whether PCOS susceptibility genes from GWAS were associated with the ovary response in PCOS women.4)To identify susceptibility genes for OHSS using GWAS.Methods:1)After screening of the two regions using our previous Chinese GWAS data,rs11031010,located in the region of follicle-stimulatin ghormone B polypeptide?FSHB?gene,was selected for further replication in 1601 PCOS cases and 1238 controls;and the associations with PCOS,endocrine and metabolic traits were assessed.The genetic risk score?GRS?was calculated based on sixteen total Chinese PCOS-risk SNPs,and the association between GRS and PCOS was evaluated.2)We scanned dyslipidemia-related genes using our previous GWAS data of PCOS and selected FADS1-FADS2 cluster for further study.Variations rs174570 was selected to represent the whole block.The case-control study was conducted in an independent cohort of 1918 PCOS cases and 1889 controls and family-based study was conducted in a set of 243 core family trios with PCOS probands.EQTL?expression quantitative trait loci?was to analyze the expression of FADS2 in individuals with differert genotypes.3)Genotyping of 15 GWAS SNPs were conducted in 879 PCOS.Ovary response was evaluated.Then,genotype-phenotype analysis was conducted.4)The first stage of OHSS-GWAS using Illumina Human Omni ZhongHua-8 bead Chip was conducted in 180 OHSS and 220 controls.The second stage using seqnome method was conducted in 103 OHSS and 1040 controls.Results:1)Rs11031010 was associated with PCOS in Han Chinese women(P=2.76×10-3),even after adjustment for age and body mass index.Meta-analysis with our previous GWAS data showed that the allele frequency difference of rs11031010between PCOS and controls reached genome-wide significance(P=4.27×10-8). PCOS women with AA and AC genotypes had a significantly higher LH level than individuals carrying the CC genotype(P=1.60×10-4).The genetic risk score based on sixteen total Chinese PCOS-risk SNPs,calculated by total number of risk alleles for each subject,was associated with the diagnosis of PCOS(P<1.00×10-4).The odd ratio?OR?of PCOS increased steadily with increasing GRS.The predictive accuracy of GRS was 0.601.2)Minor allele frequency?allele T?of rs174570 was significantly lower in PCOS cases than that in controls(P=2.17×10-3,OR=0.85),even after adjustment of BMI and age.In trios,transmission disequilibrium test?TDT?analysis revealed risk allele C of rs174570 was significantly over-transmitted(P=2.00×10-4),even after permutation corrections.Decreased expression of FADS2 was detected in PCOS cases?P=0.012?and eQTL analysis revealed the risk allele C dosage was correlated with the decline of FADS2 expression?CT vs TT,P=0.03;CC vs TT,P=0.002??3)Three genetic models were used for genotype-phenotype analysis.Rs10818854?DENND1A?was shown to be associated with the numbe of retrieved oocytes and the number of large follicles in dominant and additive model?P<0.05?.However,after the adjustment for age,BMI,starting dose of gonadotropins and total dose of gonadotropins,no SNPs were observed to be significantly correlated to ovarian response in PCOS?P>0.05?.The allele frequencies in OHSS group and non-OHSS group were not significantly different?P>0.05?.4)In the discovery stage of OHSS-GWAS,21 SNPs showed potential association with OHSS at P<1×10-4.In the replication stage,only rs1887181?MGMT/EBF3?was significantly asscociated with OHSS?P=0.037?.Conclusions:1)Variants in FSHB gene are associated with PCOS and LH levels in Han Chinese women.GRS based on 16 SNPs from PCOS GWAS is strongly associated with PCOS and plays a role in PCOS prediction.2)FADS1-FADS2 are susceptibility genes for PCOS.The expression of FADS2 is negative correlated to dosage of C allele.3)15 SNPs from GWAS were not associated with PCOS ovary response.4)A novel susceptibility gene?MGMT/EBF3?was identified for OHSS,which need further validation in multi-center studies with large sample size. |
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