A trans-ethnic genome-wide association study of uterine fibroids

Todd L. Edwards, Ayush Giri, Jacklyn N. Hellwege, Katherine E. Hartmann, Elizabeth A. Stewart, Janina M. Jeff, Michael J. Bray, Sarah A. Pendergrass, Eric S. Torstenson, Jacob M. Keaton, Sarah H. Jones, Radhika P. Gogoi, Helena Kuivaniemi, Kathryn L. Jackson, Abel N. Kho, Iftikhar Jan Kullo, Catherine A. McCarty, Hae Kyung Im, Jennifer A. Pacheco, Jyotishman PathakMarc S. Williams, Gerard Tromp, Eimear E. Kenny, Peggy L. Peissig, Joshua C. Denny, Dan M. Roden, Digna R.Velez Edwards

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

Original languageEnglish (US)
Article number511
JournalFrontiers in Genetics
Volume10
Issue numberJUN
DOIs
StatePublished - Jan 1 2019

Fingerprint

Genome-Wide Association Study
Leiomyoma
Single Nucleotide Polymorphism
Meta-Analysis
Chromosomes, Human, Pair 10
Mendelian Randomization Analysis
Logistic Models
Genome
Gene Expression
Chromosomes, Human, Pair 8
Chromosomes, Human, Pair 9
Electronic Health Records
Subcutaneous Fat
Vagina
Menopause
Genomics
Genetic Markers
Health Care Costs
Skeletal Muscle
Chromosomes

Keywords

  • Genetic architecture
  • Genetically predicted gene expression (GPGE)
  • Genome-wide association study (GWAS)
  • Meta-analysis electronic health record (EHR)
  • Trans-ethnic
  • Uterine fibroids

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Edwards, T. L., Giri, A., Hellwege, J. N., Hartmann, K. E., Stewart, E. A., Jeff, J. M., ... Edwards, D. R. V. (2019). A trans-ethnic genome-wide association study of uterine fibroids. Frontiers in Genetics, 10(JUN), [511]. https://doi.org/10.3389/fgene.2019.00511

A trans-ethnic genome-wide association study of uterine fibroids. / Edwards, Todd L.; Giri, Ayush; Hellwege, Jacklyn N.; Hartmann, Katherine E.; Stewart, Elizabeth A.; Jeff, Janina M.; Bray, Michael J.; Pendergrass, Sarah A.; Torstenson, Eric S.; Keaton, Jacob M.; Jones, Sarah H.; Gogoi, Radhika P.; Kuivaniemi, Helena; Jackson, Kathryn L.; Kho, Abel N.; Kullo, Iftikhar Jan; McCarty, Catherine A.; Im, Hae Kyung; Pacheco, Jennifer A.; Pathak, Jyotishman; Williams, Marc S.; Tromp, Gerard; Kenny, Eimear E.; Peissig, Peggy L.; Denny, Joshua C.; Roden, Dan M.; Edwards, Digna R.Velez.

In: Frontiers in Genetics, Vol. 10, No. JUN, 511, 01.01.2019.

Research output: Contribution to journalArticle

Edwards, TL, Giri, A, Hellwege, JN, Hartmann, KE, Stewart, EA, Jeff, JM, Bray, MJ, Pendergrass, SA, Torstenson, ES, Keaton, JM, Jones, SH, Gogoi, RP, Kuivaniemi, H, Jackson, KL, Kho, AN, Kullo, IJ, McCarty, CA, Im, HK, Pacheco, JA, Pathak, J, Williams, MS, Tromp, G, Kenny, EE, Peissig, PL, Denny, JC, Roden, DM & Edwards, DRV 2019, 'A trans-ethnic genome-wide association study of uterine fibroids', Frontiers in Genetics, vol. 10, no. JUN, 511. https://doi.org/10.3389/fgene.2019.00511
Edwards TL, Giri A, Hellwege JN, Hartmann KE, Stewart EA, Jeff JM et al. A trans-ethnic genome-wide association study of uterine fibroids. Frontiers in Genetics. 2019 Jan 1;10(JUN). 511. https://doi.org/10.3389/fgene.2019.00511
Edwards, Todd L. ; Giri, Ayush ; Hellwege, Jacklyn N. ; Hartmann, Katherine E. ; Stewart, Elizabeth A. ; Jeff, Janina M. ; Bray, Michael J. ; Pendergrass, Sarah A. ; Torstenson, Eric S. ; Keaton, Jacob M. ; Jones, Sarah H. ; Gogoi, Radhika P. ; Kuivaniemi, Helena ; Jackson, Kathryn L. ; Kho, Abel N. ; Kullo, Iftikhar Jan ; McCarty, Catherine A. ; Im, Hae Kyung ; Pacheco, Jennifer A. ; Pathak, Jyotishman ; Williams, Marc S. ; Tromp, Gerard ; Kenny, Eimear E. ; Peissig, Peggy L. ; Denny, Joshua C. ; Roden, Dan M. ; Edwards, Digna R.Velez. / A trans-ethnic genome-wide association study of uterine fibroids. In: Frontiers in Genetics. 2019 ; Vol. 10, No. JUN.
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T1 - A trans-ethnic genome-wide association study of uterine fibroids

AU - Edwards, Todd L.

AU - Giri, Ayush

AU - Hellwege, Jacklyn N.

AU - Hartmann, Katherine E.

AU - Stewart, Elizabeth A.

AU - Jeff, Janina M.

AU - Bray, Michael J.

AU - Pendergrass, Sarah A.

AU - Torstenson, Eric S.

AU - Keaton, Jacob M.

AU - Jones, Sarah H.

AU - Gogoi, Radhika P.

AU - Kuivaniemi, Helena

AU - Jackson, Kathryn L.

AU - Kho, Abel N.

AU - Kullo, Iftikhar Jan

AU - McCarty, Catherine A.

AU - Im, Hae Kyung

AU - Pacheco, Jennifer A.

AU - Pathak, Jyotishman

AU - Williams, Marc S.

AU - Tromp, Gerard

AU - Kenny, Eimear E.

AU - Peissig, Peggy L.

AU - Denny, Joshua C.

AU - Roden, Dan M.

AU - Edwards, Digna R.Velez

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N2 - Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

AB - Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

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