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Exome-wide association study of plasma lipids in >300,000 individuals

Liu, Dajiang J; Peloso, Gina M.; Yu, Haojie ; Butterworth, Adam S.; Mahajan, Anubha; Saleheen, Danish; Franks, Paul LU ; Renström, Frida LU ; V Varga, Tibor LU and Groop, Leif LU , et al. (2017) In Nature Genetics 49(12). p.1758-1766
Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some... (More)
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. (Less)
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Nature Genetics
volume
49
issue
12
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85035766416
  • wos:000416480600016
ISSN
1546-1718
DOI
10.1038/ng.3977
language
English
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yes
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eb1754d7-cef4-4496-8250-fa93feaabdf2
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2017-12-12 08:39:18
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2018-08-12 04:41:16
@article{eb1754d7-cef4-4496-8250-fa93feaabdf2,
  abstract     = {We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.},
  author       = {Liu, Dajiang J and Peloso, Gina M. and Yu, Haojie  and Butterworth, Adam S. and Mahajan, Anubha and Saleheen, Danish and Franks, Paul and Renström, Frida and V Varga, Tibor and Groop, Leif and Melander, Olle and Orho-Melander, Marju},
  issn         = {1546-1718},
  language     = {eng},
  number       = {12},
  pages        = {1758--1766},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Exome-wide association study of plasma lipids in >300,000 individuals},
  url          = {http://dx.doi.org/10.1038/ng.3977},
  volume       = {49},
  year         = {2017},
}