Linkage and Association Analyses of Longitudinally Measured Lipid Phenotypes in Adolescence

Abstract

The genetic basis of cardiovascular disease (CVD) is complex and still largely elusive. Plasma lipid concentrations are well-established risk factors for cardiovascular disease (CVD), and have adult heritabilities ranging from 0.48 to 0.87. Estimates for adolescents are slightly higher (range 0.71 to 0.82). To identify loci affecting lipid concentrations across adolescence, we analyzed longitudinal lipid data in a sample of 134 monozygotic and 626 dizygotic twin pairs at ages twelve, fourteen and sixteen, and their siblings, from 760 Australian families. Univariate linkage analysis for each phenotype and time point was supplemented by multivariate analysis across the time points. A genome-wide association scan was also performed on a subset of the subjects (N= 441). The strongest linkage was seen for triglycerides on chromosome 6p24.3 (multivariate –log10p= 6.81; equivalent LOD = 6.13;p= 1.55 × 10–7). Significant linkage was also found for LDL cholesterol on chromosome 2q35 (multivariate –log10p= 5.59; equivalent LOD = 4.53;p= 2.57 × 10–6). In the association analysis, rs10503840 on 8p21.1 was significantly associated with total cholesterol levels at age fourteen (p= 8.24 × 10–7, estimated significance threshold 2.45 × 10–6). Association atp< 2.25 × 10–6was also found between triglycerides at age 12 and rs10507266, in an intron ofTHRAP2(MIM 608771) on 12q24.21; and between HDL-C at age 14 and rs10506325 in an intergenic region of 12q13.13. Suggestive evidence of association at ages twelve and fourteen was found between HDL-C and rs10492859 on 16q23 (p= 2.42 × 10–5and 2.77 × 10–4, respectively). Further longitudinal genetic studies of cardiovascular risk factors, focused on critical periods of development or change, are needed.

Novel Locus FER Is Associated With Serum HMW Adiponectin Levels

“…Another locus near the KCNK9 gene on chromosome 8q24 also showed suggestive association with HMW adiponectin levels. Of note, in a previous genome-wide scan this locus was related to the levels of triglycerides (22). SNPs in genes ARL15 (rs4311394) and CDH13 (rs3865188 and rs7195409) were recently associated with total or HMW adiponectin levels (11,12,14).…”

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins

“…A GWAS conducted by Middelberg RP et al ( 18 ) for plasma cholesterol found genes LPL, LIPC, CETP associated with HDL-C level and CELSR2, APOB, TOMM40 with LDL-C level. Another two GWAS studies identified SRGAP2, HOXC13 and CD47, DUSP4 that were associated with HDL-C and TC level, respectively ( 19 , 20 ).…”

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome

“…In this context, it should be noted that the chromosomal region, 6p25.3 to 6p24.3, has already been associated with TG levels (Middelberg et al, 2008), total body fat mass in females (Lei et al, 2009) and neuroendocrine carcinomas of uterus and ovary (Aboura et al, 2009;Mhawech-Fauceglia et al, 2008). The genetic variants we investigated -like another important polymorphism in the F13A1 gene (rs5985, Val34Leu) -might also have effects on cell specific expression, stability or availability as well as activity of the protein (Muszbek et al, 2008).…”