Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

TitleMeta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.
Publication TypeJournal Article
Year of Publication2016
Authorsvan Leeuwen, EM, Sabo, A, Bis, JC, Huffman, JE, Manichaikul, A, Smith, AV, Feitosa, MF, Demissie, S, Joshi, PK, Duan, Q, Marten, J, van Klinken, JB, Surakka, I, Nolte, IM, Zhang, W, Mbarek, H, Li-Gao, R, Trompet, S, Verweij, N, Evangelou, E, Lyytikäinen, L-P, Tayo, BO, Deelen, J, van der Most, PJ, van der Laan, SW, Arking, DE, Morrison, A, Dehghan, A, Franco, OH, Hofman, A, Rivadeneira, F, Sijbrands, EJ, Uitterlinden, AG, Mychaleckyj, JC, Campbell, A, Hocking, LJ, Padmanabhan, S, Brody, JA, Rice, KM, White, CC, Harris, T, Isaacs, A, Campbell, H, Lange, LA, Rudan, I, Kolcic, I, Navarro, P, Zemunik, T, Salomaa, V, Kooner, AS, Kooner, JS, Lehne, B, Scott, WR, Tan, S-T, de Geus, EJ, Milaneschi, Y, Penninx, BWJH, Willemsen, G, de Mutsert, R, Ford, I, Gansevoort, RT, Segura-Lepe, MP, Raitakari, OT, Viikari, JS, Nikus, K, Forrester, T, McKenzie, CA, de Craen, AJM, de Ruijter, HM, Pasterkamp, G, Snieder, H, Oldehinkel, AJ, P Slagboom, E, Cooper, RS, Kähönen, M, Lehtimäki, T, Elliott, P, van der Harst, P, J Jukema, W, Mook-Kanamori, DO, Boomsma, DI, Chambers, JC, Swertz, M, Ripatti, S, van Dijk, KWillems, Vitart, V, Polasek, O, Hayward, C, Wilson, JG, Wilson, JF, Gudnason, V, Rich, SS, Psaty, BM, Borecki, IB, Boerwinkle, E, Rotter, JI, L Cupples, A, van Duijn, CM
Corporate Authors,
JournalJ Med Genet
Volume53
Issue7
Pagination441-9
Date Published2016 Jul
ISSN1468-6244
Abstract

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

DOI10.1136/jmedgenet-2015-103439
Alternate JournalJ. Med. Genet.
PubMed ID27036123
PubMed Central IDPMC4941146
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
N01-HC-95166 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
N01-HC-95163 / HL / NHLBI 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
HHSN268201100008 / HL / NHLBI NIH HHS / United States
N01-HC-95169 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201100005 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI 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
N01-HC-95167 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
HHSN268201100011 / HL / NHLBI NIH HHS / United States
R01 HL088215 / HL / NHLBI NIH HHS / United States
CSO_CZD/16/6/4 / / Chief Scientist Office / United Kingdom
N01-HC-95160 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN271201200022 / AG / NIA NIH HHS / United States
N01-HC-95161 / HL / NHLBI 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
UL1 TR000040 / TR / NCATS NIH HHS / United States
HHSN268201100009 / HL / NHLBI NIH HHS / United States
N01-HC-95165 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL087700 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01-HC-95164 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States