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Genetic Variants Associated with Circulating Parathyroid Hormone.

TitleGenetic Variants Associated with Circulating Parathyroid Hormone.
Publication TypeJournal Article
Year of Publication2017
AuthorsRobinson-Cohen C, Lutsey PL, Kleber ME, Nielson CM, 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 L-C, Wong HSuen, Lai D, Peacock M, Hannemann A, Völker U, Homuth G, Nauk M, Murgia F, Pattee JW, Orwoll E, Zmuda JM, Riancho JAntonio, 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 JJ, Wallaschofski H, Pankow JS, de Boer IH
Secondary AuthorsKestenbaum B
JournalJ Am Soc Nephrol
Volume28
Issue5
Pagination1553-1565
Date Published2017 May
ISSN1533-3450
KeywordsAdult, Aged, Europe, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Parathyroid Hormone, Polymorphism, Single Nucleotide
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 (=22,653 and =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 (=4.2 × 10), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within (=6.6 × 10), rs219779 adjacent to (=3.5 × 10), rs4443100 near (=8.7 × 10), and rs73186030 near (=4.8 × 10). 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.

DOI10.1681/ASN.2016010069
Alternate JournalJ Am Soc Nephrol
PubMed ID27927781
PubMed Central IDPMC5407713
Grant ListHHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
U01 AG027810 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 MH089951 / MH / NIMH NIH HHS / United States
K24 DK103986 / DK / NIDDK NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
U01 DK094176 / DK / NIDDK NIH HHS / United States
R01 HL103706 / HL / NHLBI NIH HHS / United States
R01 AR046838 / AR / NIAMS NIH HHS / United States
R01 MH081802 / MH / NIMH NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
R01 HL071251 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL071259 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
RC2 MH089995 / MH / NIMH NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
UL1 TR000128 / TR / NCATS NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
R01 HL071250 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 AG042124 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U01 AG042145 / AG / NIA NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
R01 AG041517 / AG / NIA NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL071051 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
K01 DK109019 / DK / NIDDK NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
U01 AG042168 / AG / NIA NIH HHS / United States
K24 DK106414 / DK / NIDDK NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
U01 AG042140 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
U01 DK094157 / DK / NIDDK NIH HHS / United States
K01 AR062655 / AR / NIAMS NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
/ / Wellcome Trust / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL071258 / HL / NHLBI NIH HHS / United States
U01 AG042143 / AG / NIA NIH HHS / United States
U01 AG042139 / AG / NIA NIH HHS / United States
T32 GM108557 / GM / NIGMS NIH HHS / United States
U01 AR066160 / AR / NIAMS NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States