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Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.
Wednesday,2015-03-04 12:59 America/Los_Angeles — zdrager
| Title | Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Lange, LA, Hu, Y, Zhang, H, Xue, C, Schmidt, EM, Tang, Z-Z, Bizon, C, Lange, EM, Smith, JD, Turner, EH, Jun, G, Kang, HMin, Peloso, G, Auer, P, Li, K-P, Flannick, J, Zhang, J, Fuchsberger, C, Gaulton, K, Lindgren, C, Locke, A, Manning, A, Sim, X, Rivas, MA, Holmen, OL, Gottesman, O, Lu, Y, Ruderfer, D, Stahl, EA, Duan, Q, Li, Y, Durda, P, Jiao, S, Isaacs, A, Hofman, A, Bis, JC, Correa, A, Griswold, ME, Jakobsdottir, J, Smith, AV, Schreiner, PJ, Feitosa, MF, Zhang, Q, Huffman, JE, Crosby, J, Wassel, CL, Do, R, Franceschini, N, Martin, LW, Robinson, JG, Assimes, TL, Crosslin, DR, Rosenthal, EA, Tsai, M, Rieder, MJ, Farlow, DN, Folsom, AR, Lumley, T, Fox, ER, Carlson, CS, Peters, U, Jackson, RD, van Duijn, CM, Uitterlinden, AG, Levy, D, Rotter, JI, Taylor, HA, Gudnason, V, Siscovick, DS, Fornage, M, Borecki, IB, Hayward, C, Rudan, I, Y Chen, E, Bottinger, EP, Loos, RJF, Sætrom, P, Hveem, K, Boehnke, M, Groop, L, McCarthy, M, Meitinger, T, Ballantyne, CM, Gabriel, SB, O'Donnell, CJ, Post, WS, North, KE, Reiner, AP, Boerwinkle, E, Psaty, BM, Altshuler, D, Kathiresan, S, Lin, D-Y, Jarvik, GP, Cupples, AL, Kooperberg, C, Wilson, JG, Nickerson, DA, Abecasis, GR, Rich, SS, Tracy, RP, Willer, CJ |
| Corporate/Institutional Authors | NHLBI Grand Opportunity Exome Sequencing Project |
| Journal | Am J Hum Genet |
| Volume | 94 |
| Issue | 2 |
| Pagination | 233-45 |
| Date Published | 2014 Feb 06 |
| ISSN | 1537-6605 |
| Keywords | Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases |
| Abstract | <p>Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.</p> |
| DOI | 10.1016/j.ajhg.2014.01.010 |
| Alternate Journal | Am. J. Hum. Genet. |
| PubMed ID | 24507775 |
| PubMed Central ID | PMC3928660 |
| Grant List | R01 CA082659 / CA / NCI NIH HHS / United States RC2 HL102923 / HL / NHLBI NIH HHS / United States R01 HL107816 / HL / NHLBI NIH HHS / United States R01 HL109946 / HL / NHLBI NIH HHS / United States RC2 HL102926 / HL / NHLBI NIH HHS / United States R01 HL67406 / HL / NHLBI NIH HHS / United States RC2 HL-102926 / HL / NHLBI NIH HHS / United States U01 HG007416 / HG / NHGRI NIH HHS / United States R01HL107816 / HL / NHLBI NIH HHS / United States RC2 HL-102923 / HL / NHLBI NIH HHS / United States P30 DK079637 / DK / NIDDK NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States T32 HL007208 / HL / NHLBI NIH HHS / United States R00HL94535 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States RC2 HL-102924 / HL / NHLBI NIH HHS / United States RC2 HL102924 / HL / NHLBI NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States P20 MD006899 / MD / NIMHD NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 HL067406 / HL / NHLBI NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom R00 HL094535 / HL / NHLBI NIH HHS / United States MC_PC_U127561128 / / Medical Research Council / United Kingdom U01 DK062370 / DK / NIDDK NIH HHS / United States UC2 HL102924 / HL / NHLBI NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States RC2 HL103010 / HL / NHLBI NIH HHS / United States RC2 HL-103010 / HL / NHLBI NIH HHS / United States RC2 HL102925 / HL / NHLBI NIH HHS / United States UC2 HL102925 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States |