Linkage analysis incorporating gene-age interactions identifies seven novel lipid loci: the Family Blood Pressure Program.

 
TitleLinkage analysis incorporating gene-age interactions identifies seven novel lipid loci: the Family Blood Pressure Program.
Publication TypeJournal Article
Year of Publication2014
AuthorsSimino, J, Kume, R, Kraja, AT, Turner, ST, Hanis, CL, Sheu, WH-H, Chen, Y-DIda, Jaquish, CE, Cooper, RS, Chakravarti, A, Quertermous, T, Boerwinkle, E, Hunt, SC, Rao, DC
JournalAtherosclerosis
Volume235
Issue1
Pagination84-93
Date Published2014 Jul
ISSN1879-1484
Abstract

OBJECTIVE: To detect novel loci with age-dependent effects on fasting (≥ 8 h) levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides using 3600 African Americans, 1283 Asians, 3218 European Americans, and 2026 Mexican Americans from the Family Blood Pressure Program (FBPP).

METHODS: Within each subgroup (defined by network, race, and sex), we employed stepwise linear regression (retention p ≤ 0.05) to adjust lipid levels for age, age-squared, age-cubed, body-mass-index, current smoking status, current drinking status, field center, estrogen therapy (females only), as well as antidiabetic, antihypertensive, and antilipidemic medication use. For each trait, we pooled the standardized male and female residuals within each network and race and fit a generalized variance components model that incorporated gene-age interactions. We conducted FBPP-wide and race-specific meta-analyses by combining the p-values of each linkage marker across subgroups using a modified Fisher's method.

RESULTS: We identified seven novel loci with age-dependent effects; four total cholesterol loci from the meta-analysis of Mexican Americans (on chromosomes 2q24.1, 4q21.21, 8q22.2, and 12p11.23) and three high-density lipoprotein loci from the meta-analysis of all FBPP subgroups (on chromosomes 1p12, 14q11.2, and 21q21.1). These loci lacked significant genome-wide linkage or association evidence in the literature and had logarithm of odds (LOD) score ≥ 3 in the meta-analysis with LOD ≥ 1 in at least two network and race subgroups (exclusively of non-European descent).

CONCLUSION: Incorporating gene-age interactions into the analysis of lipids using multi-ethnic cohorts can enhance gene discovery. These interaction loci can guide the selection of families for sequencing studies of lipid-associated variants.

DOI10.1016/j.atherosclerosis.2014.04.008
Alternate JournalAtherosclerosis
PubMed ID24819747
PubMed Central IDPMC4322916
Grant ListHL54471 / HL / NHLBI NIH HHS / United States
HL54473 / HL / NHLBI NIH HHS / United States
HL54481 / HL / NHLBI NIH HHS / United States
HL54498 / HL / NHLBI NIH HHS / United States
HL54512 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 GM028719 / GM / NIGMS NIH HHS / United States
R01 HL055673 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL107552 / HL / NHLBI NIH HHS / United States
R01 HL111249 / HL / NHLBI NIH HHS / United States
R01 HL118305 / HL / NHLBI NIH HHS / United States
R01HL055673 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
R01HL107552 / HL / NHLBI NIH HHS / United States
R01HL111249 / HL / NHLBI NIH HHS / United States
R01HL118305 / HL / NHLBI NIH HHS / United States
R21 HL095054 / HL / NHLBI NIH HHS / United States
R21 HL095054 / HL / NHLBI NIH HHS / United States
U01 HL054471 / HL / NHLBI NIH HHS / United States
U01 HL054473 / HL / NHLBI NIH HHS / United States
U01 HL054498 / HL / NHLBI NIH HHS / United States
U10 HL054481 / HL / NHLBI NIH HHS / United States
U10 HL054512 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States