Transethnic Evaluation Identifies Low-Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations

Jaeyoung Hong, Kathryn E. Hatchell, Jonathan P. Bradfield, Andrew Bjonnes, Alessandra Chesi, Chao Qiang Lai, Carl D. Langefeld, Lingyi Lu, Yingchang Lu, Pamela L. Lutsey, Solomon K. Musani, Mike A. Nalls, Cassianne Robinson-Cohen, Jeffery D. Roizen, Richa Saxena, Katherine L. Tucker, Julie T. Ziegler, Dan E. Arking, Joshua C. Bis, Eric BoerwinkleErwin P. Bottinger, Donald W. Bowden, Vicente Gilsanz, Denise K. Houston, Heidi J. Kalkwarf, Andrea Kelly, Joan M. Lappe, Yongmei Liu, Erin D. Michos, Sharon E. Oberfield, Nicholette D. Palmer, Jerome I. Rotter, Bishwa Sapkota, John A. Shepherd, James G. Wilson, Saonli Basu, Ian H. De Boer, Jasmin Divers, Barry I. Freedman, Struan F.A. Grant, Hakon Hakanarson, Tamara B. Harris, Bryan R. Kestenbaum, Stephen B. Kritchevsky, Ruth J.F. Loos, Jill M. Norris, Arnita F. Norwood, Jose M. Ordovas, James S. Pankow, Bruce M. Psaty, Dharambir K. Sanghera, Lynne E. Wagenknecht, Babette S. Zemel, James Meigs, Josée Dupuis, Jose C. Florez, Thomas Wang, Ching Ti Liu, Corinne D. Engelman, Liana K. Billings

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Context Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures Blood concentrations of 25(OH)D were measured for all participants. Results Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

Original languageEnglish (US)
Pages (from-to)1380-1392
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
StatePublished - Apr 1 2018

Bibliographical note

Funding Information:
The AADHS was supported by NIH grants R01-DK-071891 from the National Institute of Diabetes and Digestive and Kidney Diseases and General Clinical Re search Center of Wake Forest School of Medicine grant M01-RR-07122.

Funding Information:
This research was supported by the Intramural Research Program of the NIA, contracts N01AG62101, N01AG62103, and N01AG62106; and NIA grant R01 AG028050; and National Institute of Nursing Research grant R01 NR012459. Assessment of 25-hydroxyvitamin D was funded by NIA grant R01 AG029364. The GWAS was funded by NIA grant R01 AG032098 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research. The Center for Inherited Disease Research is fullyfundedthroughafederalcontractfromtheNIHtoTheJohns Hopkins University, contract number HHSN268200782096C.

Funding Information:
This CHS research was supported by NHLBI contracts HHSN268200800007C and HHSN268201200036C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114, with additional contribution from the National Institute of Neurologic Disorders and Stroke. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical & Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding Information:
This research was financially supported by an Institute Development Award from CHOP, a Research Development Award from the Cotswold Foundation, and NIH grant R01 HD056465.

Funding Information:
This work was supported by the NIH (grant numbers HD58886 and HD076321); the Eunice Kennedy Shriver National Institute of Child Health and Human Development contracts N01-HD-1-3228, N01-HD-1-3329, N01-HD-1-3330, N01-HD-1-3331, N01-HD-1-3332, and N01-HD-1-3333; and the NIH Clinical and Translational Science Award program (grant 8 UL1 TR000077).

Funding Information:
ARIC’s contribution to this project was supported by NHLBI R01 HL103706 and contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; Office of Dietary Supplements grant number R01 HL103706-S1; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research.

Funding Information:
This work was supported by NIH grants R01DK082766, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and NOT-HG-11-009, funded by the National Human Genome Research Institute. This work was also partly supported by VPR Bridge Grant and Harold Hamm Enrichment Grant from the University of Oklahoma Health Sciences Center. The authors thank all the participants of the Asian Indian Diabetic Heart Study/Sikh Diabetes Study and are grateful for their contribution to this study.

Funding Information:
Financial Support: J.H., J. Dupuis, J.M., and C.-T.L. were supported by National Institutes of Health (NIH) grant R01 DK078616. K.E.H. was supported by a National Library of Medicine training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). L.K.B. was supported by National Research Service Award Institutional Training Grant T32 DK007028-35 to Massachusetts General Hospital, the Endocrine Society’s Lilly Scholar’s Award, an NIH Loan Repayment Award, and the NorthShore University HealthSystem Auxiliary Research Scholar Award. M.A.N.’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), NIH, Bethesda, MD.

Funding Information:
The IRASFS was supported by HL-060944, HL-061019, and HL-060919. The provision of genotyping was supported by DK085175 (GUARDIAN) and in part by UL1-TR-000124 (Clinical & Translational Science Institute) and DK063491 (Diabetes Research Center). Vitamin D measurement in the IRASFS was supported by American Diabetes Association award 25-15105.

Funding Information:
MESA and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169; UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420; UL1-TR-001881; and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and MIT (Boston, Massachusetts) with the Affymetrix Genome-Wide Human SNP Array 6.0. Support for the Mineral Metabolite data set was provided by grant HL096875.

Funding Information:
Research reported in this publication was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH under award number R56HL124004 to C.D.E. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The JHS is supported by contracts HSN268201300046C, HSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Institute on Minority Health and Health Disparities.

Publisher Copyright:
© 2018 Endocrine Society.


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