Dataset Information

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

ABSTRACT: Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

SUBMITTER: Du Z

PROVIDER: S-EPMC6960456 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Du Zhaohui Z Weinhold Niels N Song Gregory Chi GC Rand Kristin A KA Van Den Berg David J DJ Hwang Amie E AE Sheng Xin X Hom Victor V Ailawadhi Sikander S Nooka Ajay K AK Singhal Seema S Pawlish Karen K Peters Edward S ES Bock Cathryn C Mohrbacher Ann A Stram Alexander A Berndt Sonja I SI Blot William J WJ Casey Graham G Stevens Victoria L VL Kittles Rick R Goodman Phyllis J PJ Diver W Ryan WR Hennis Anselm A Nemesure Barbara B Klein Eric A EA Rybicki Benjamin A BA Stanford Janet L JL Witte John S JS Signorello Lisa L John Esther M EM Bernstein Leslie L Stroup Antoinette M AM Stephens Owen W OW Zangari Maurizio M Van Rhee Frits F Olshan Andrew A Zheng Wei W Hu Jennifer J JJ Ziegler Regina R Nyante Sarah J SJ Ingles Sue Ann SA Press Michael F MF Carpten John David JD Chanock Stephen J SJ Mehta Jayesh J Colditz Graham A GA Wolf Jeffrey J Martin Thomas G TG Tomasson Michael M Fiala Mark A MA Terebelo Howard H Janakiraman Nalini N Kolonel Laurence L Anderson Kenneth C KC Le Marchand Loic L Auclair Daniel D Chiu Brian C-H BC Ziv Elad E Stram Daniel D Vij Ravi R Bernal-Mizrachi Leon L Morgan Gareth J GJ Zonder Jeffrey A JA Huff Carol Ann CA Lonial Sagar S Orlowski Robert Z RZ Conti David V DV Haiman Christopher A CA Cozen Wendy W

Blood advances 20200101 1

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibilit ...[more]

PMID: 31935283

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Project description:BackgroundPolycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.ResultsThe study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.ConclusionsGenetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Dataset Information

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Publications

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Similar Datasets

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