Transethnic evaluation identifies low-frequency loci associated with 25-hydroxyvitamin D concentrations

Authors: HONG, JAEYOUNG - Boston University; HATCHELL, KATHRYN - University Of Wisconsin; BRADFIELD, JONATHAN - The Children'S Hospital Of Philadelphia; BJONNES, ANDREW - Massachusetts General Hospital; CHESI, ALESSANDRA - The Children'S Hospital Of Philadelphia; Lai, Chao Qiang; LANGEFELD, CARL - Wake Forest University; LU, LINGYI - Wake Forest University; LU, YINGCHANG - The Icahn School Of Medicine At Mount Sinai; LUTSEY, PAMELA - University Of Minnesota; MUSANI, SOLMOMON - University Of Mississippi; NALLS, MIKE - Data Tecnica International; ROBINSON-COHEN, CASSIANNE - Vanderbilt University; ROIZEN, JEFFERY - The Children'S Hospital Of Philadelphia; SAXENA, RICHA - Massachusetts General Hospital; TUCKER, KATHERINE - University Of Massachusetts; ZIEGLER, JULIE - Wake Forest University; ARKING, DAN - Johns Hopkins University; BIS, JOSHUA - University Of Washington; BOERWINKLE, ERIC - University Of Texas; BOTTINGER, ERWIN - The Icahn School Of Medicine At Mount Sinai; BOWDEN, DONALD - Wake Forest University; GILSANZ, VINCENTE - University Of Southern California; HOUSTON, DENISE - Wake Forest University; KALKWARF, HEIDI - Children'S Hospital - Cincinnati, Ohio; KELLY, ANDREA - The Children'S Hospital Of Philadelphia; LAPPE, JOAN - Creighton University; LIU, YONGMEI - Wake Forest University; MICHOS, ERIN - Johns Hopkins University; OBERFIELD, SHARON - Columbia University; PALMER, NICHOLETTE - Wake Forest University; ROTTER, JEROME - Harbor-Ucla Medical Center; SAPKOTA, BISHWA - University Of Oklahoma; SHEPHERD, JOHN - University Of California; WILSON, JAMES - University Of Mississippi; BASU, SAONLI - University Of Minnesota; DE BOER, IAN - University Of Washington; DIVERS, JASMIN - Wake Forest University; FREEDMAN, BARRY - Wake Forest University; GRANT, STRUAN - The Children'S Hospital Of Philadelphia; HAKANARSON, HAKON - The Children'S Hospital Of Philadelphia; HARRIS, TAMARA - National Institute On Aging (NIA, NIH); KESTENBAUM, BRYAN - University Of Washington; KRITCHEVSKY, STEPHEN - Wake Forest University; LOOS, RUTH - The Icahn School Of Medicine At Mount Sinai; NORRIS, JILL - University Of Colorado; NORWOOD, ARNITA - University Of Mississippi Medical Center; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PANKOW, JAMES - University Of Minnesota; PSATY, BRUCE - University Of Washington; SANGHERA, DHARAMBIR - University Of Oklahoma; WAGENKNECHT, LYNNE - Wake Forest University; ZEMEL, BABETTE - The Children'S Hospital Of Philadelphia; MEIGS, JAMES - Harvard University; DUPIUS, JOSEE - Boston University; FLOREZ, JOSE - Broad Institute Of Mit/harvard; WANG, THOMAS - Vanderbilt University; LIU, CHING-TI - Boston University; ENGELMAN, CORINNE - University Of Wisconsin; BILLINGS, LIANA - Northshore University Health System

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2018
Publication Date: 1/9/2018
Citation: Hong, J., Hatchell, K.E., Bradfield, J.P., Bjonnes, A., Chesi, A., Lai, C., Langefeld, C.D., Lu, L., Lu, Y., Lutsey, P.L., Musani, S.K., Nalls, M.A., Robinson-Cohen, C., Roizen, J.D., Saxena, R., Tucker, K.L., Ziegler, J.T., Arking, D.E., Bis, J.C., Boerwinkle, E., Bottinger, E.P., Bowden, D.W., Gilsanz, V., Houston, D.K., Kalkwarf, H.J., Kelly, A., Lappe, J.M., Liu, Y., Michos, E.D., Oberfield, S.E., Palmer, N.D., Rotter, J.I., Sapkota, B., Shepherd, J.A., Wilson, J.G., Basu, S., De Boer, I.H., Divers, J., Freedman, B.I., Grant, S.F., Hakanarson, H., Harris, T.B., Kestenbaum, B.R., Kritchevsky, S.B., Loos, R.J., Norris, J.M., Norwood, A.F., Ordovas, J.M., Pankow, J.S., Psaty, B.M., Sanghera, D.K., Wagenknecht, L.E., Zemel, B.S., Meigs, J., Dupius, J., Florez, J.C., Wang, T.J., Liu, C., Engelman, C.D., Billings, L.K. 2018. Transethnic evaluation identifies low-frequency loci associated with 25-hydroxyvitamin D concentrations. Journal of Clinical Endocrinology and Metabolism. 103(4):1380-1392. https://doi.org/10.1210/jc.2017-01802.
DOI: https://doi.org/10.1210/jc.2017-01802

Interpretive Summary: 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. These populations are particularly vulnerable to vitamin D inadequacy because skin-pigmentation affects the vitamin D conversion due to sunlight exposure. This study was designed to identify genetic variants that affect vitamin D concentrations in 8,541 African American, 3,485 Hispanic American and 16,124 European individuals. Genetic variants were identified in the GC and DHCR7 genes that were shared by both Africans and Hispanic Americans and one variant near the KIF4B gene that was specific to African Americans. These findings indicate that the genetic basis of vitamin D inadequacies is population specific.

Technical Abstract: 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.