Genetic variants associated with circulating parathyroid hormone

Cassianne Robinson-Cohen, Pamela L. Lutsey, Marcus E. Kleber, Carrie Nielson, Braxton D. Mitchell, Joshua C. Bis, Karen M. Eny, Laura Portas, Joel Eriksson, Mattias Lorentzon, Daniel L. Koller, Yuri Milaneschi, Alexander Teumer, Stefan Pilz, Maria Nethander, Elizabeth Selvin, Weihong Tang, Lu Chen Weng, Hoi Suen Wong, Dongbing LaiMunro Peacock, Anke Hannemann, Uwe Völker, Georg Homuth, Matthias Nauk, Federico Murgia, Jack W. Pattee, Eric Orwoll, Joseph M. Zmuda, Jose Antonio Riancho, Myles Wolf, Frances Williams, Brenda Penninx, Michael J. Econs, Kathleen A. Ryan, Claes Ohlsson, Andrew D. Paterson, Bruce M. Psaty, David S. Siscovick, Jerome I. Rotter, Mario Pirastu, Elizabeth Streeten, Winfried März, Caroline Fox, Josef Coresh, Henri Wallaschofski, James S. Pankow, Ian H. De Boer, Bryan Kestenbaum

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Original languageEnglish (US)
Pages (from-to)1553-1565
Number of pages13
JournalJournal of the American Society of Nephrology
Volume28
Issue number5
DOIs
StatePublished - May 1 2017

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Parathyroid Hormone
Single Nucleotide Polymorphism
Serum
Secondary Hyperparathyroidism
Dihydroxycholecalciferols
Primary Hyperparathyroidism
Genome-Wide Association Study
Bone Diseases
Vitamin D
Genes
Cohort Studies
Alleles
Hormones
Hypertension
Calcium
Kidney
Mortality
Enzymes

ASJC Scopus subject areas

  • Nephrology

Cite this

Robinson-Cohen, C., Lutsey, P. L., Kleber, M. E., Nielson, C., Mitchell, B. D., Bis, J. C., ... Kestenbaum, B. (2017). Genetic variants associated with circulating parathyroid hormone. Journal of the American Society of Nephrology, 28(5), 1553-1565. https://doi.org/10.1681/ASN.2016010069

Genetic variants associated with circulating parathyroid hormone. / Robinson-Cohen, Cassianne; Lutsey, Pamela L.; Kleber, Marcus E.; Nielson, Carrie; Mitchell, Braxton D.; Bis, Joshua C.; Eny, Karen M.; Portas, Laura; Eriksson, Joel; Lorentzon, Mattias; Koller, Daniel L.; Milaneschi, Yuri; Teumer, Alexander; Pilz, Stefan; Nethander, Maria; Selvin, Elizabeth; Tang, Weihong; Weng, Lu Chen; Wong, Hoi Suen; Lai, Dongbing; Peacock, Munro; Hannemann, Anke; Völker, Uwe; Homuth, Georg; Nauk, Matthias; Murgia, Federico; Pattee, Jack W.; Orwoll, Eric; Zmuda, Joseph M.; Riancho, Jose Antonio; Wolf, Myles; Williams, Frances; Penninx, Brenda; Econs, Michael J.; Ryan, Kathleen A.; Ohlsson, Claes; Paterson, Andrew D.; Psaty, Bruce M.; Siscovick, David S.; Rotter, Jerome I.; Pirastu, Mario; Streeten, Elizabeth; März, Winfried; Fox, Caroline; Coresh, Josef; Wallaschofski, Henri; Pankow, James S.; De Boer, Ian H.; Kestenbaum, Bryan.

In: Journal of the American Society of Nephrology, Vol. 28, No. 5, 01.05.2017, p. 1553-1565.

Research output: Contribution to journalArticle

Robinson-Cohen, C, Lutsey, PL, Kleber, ME, Nielson, C, Mitchell, BD, Bis, JC, Eny, KM, Portas, L, Eriksson, J, Lorentzon, M, Koller, DL, Milaneschi, Y, Teumer, A, Pilz, S, Nethander, M, Selvin, E, Tang, W, Weng, LC, Wong, HS, Lai, D, Peacock, M, Hannemann, A, Völker, U, Homuth, G, Nauk, M, Murgia, F, Pattee, JW, Orwoll, E, Zmuda, JM, Riancho, JA, Wolf, M, Williams, F, Penninx, B, Econs, MJ, Ryan, KA, Ohlsson, C, Paterson, AD, Psaty, BM, Siscovick, DS, Rotter, JI, Pirastu, M, Streeten, E, März, W, Fox, C, Coresh, J, Wallaschofski, H, Pankow, JS, De Boer, IH & Kestenbaum, B 2017, 'Genetic variants associated with circulating parathyroid hormone', Journal of the American Society of Nephrology, vol. 28, no. 5, pp. 1553-1565. https://doi.org/10.1681/ASN.2016010069
Robinson-Cohen, Cassianne ; Lutsey, Pamela L. ; Kleber, Marcus E. ; Nielson, Carrie ; Mitchell, Braxton D. ; Bis, Joshua C. ; Eny, Karen M. ; Portas, Laura ; Eriksson, Joel ; Lorentzon, Mattias ; Koller, Daniel L. ; Milaneschi, Yuri ; Teumer, Alexander ; Pilz, Stefan ; Nethander, Maria ; Selvin, Elizabeth ; Tang, Weihong ; Weng, Lu Chen ; Wong, Hoi Suen ; Lai, Dongbing ; Peacock, Munro ; Hannemann, Anke ; Völker, Uwe ; Homuth, Georg ; Nauk, Matthias ; Murgia, Federico ; Pattee, Jack W. ; Orwoll, Eric ; Zmuda, Joseph M. ; Riancho, Jose Antonio ; Wolf, Myles ; Williams, Frances ; Penninx, Brenda ; Econs, Michael J. ; Ryan, Kathleen A. ; Ohlsson, Claes ; Paterson, Andrew D. ; Psaty, Bruce M. ; Siscovick, David S. ; Rotter, Jerome I. ; Pirastu, Mario ; Streeten, Elizabeth ; März, Winfried ; Fox, Caroline ; Coresh, Josef ; Wallaschofski, Henri ; Pankow, James S. ; De Boer, Ian H. ; Kestenbaum, Bryan. / Genetic variants associated with circulating parathyroid hormone. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 5. pp. 1553-1565.
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abstract = "Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7{\%}higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.",
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T1 - Genetic variants associated with circulating parathyroid hormone

AU - Robinson-Cohen, Cassianne

AU - Lutsey, Pamela L.

AU - Kleber, Marcus E.

AU - Nielson, Carrie

AU - Mitchell, Braxton D.

AU - Bis, Joshua C.

AU - Eny, Karen M.

AU - Portas, Laura

AU - Eriksson, Joel

AU - Lorentzon, Mattias

AU - Koller, Daniel L.

AU - Milaneschi, Yuri

AU - Teumer, Alexander

AU - Pilz, Stefan

AU - Nethander, Maria

AU - Selvin, Elizabeth

AU - Tang, Weihong

AU - Weng, Lu Chen

AU - Wong, Hoi Suen

AU - Lai, Dongbing

AU - Peacock, Munro

AU - Hannemann, Anke

AU - Völker, Uwe

AU - Homuth, Georg

AU - Nauk, Matthias

AU - Murgia, Federico

AU - Pattee, Jack W.

AU - Orwoll, Eric

AU - Zmuda, Joseph M.

AU - Riancho, Jose Antonio

AU - Wolf, Myles

AU - Williams, Frances

AU - Penninx, Brenda

AU - Econs, Michael J.

AU - Ryan, Kathleen A.

AU - Ohlsson, Claes

AU - Paterson, Andrew D.

AU - Psaty, Bruce M.

AU - Siscovick, David S.

AU - Rotter, Jerome I.

AU - Pirastu, Mario

AU - Streeten, Elizabeth

AU - März, Winfried

AU - Fox, Caroline

AU - Coresh, Josef

AU - Wallaschofski, Henri

AU - Pankow, James S.

AU - De Boer, Ian H.

AU - Kestenbaum, Bryan

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N2 - Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

AB - Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

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