A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

近期的全基因组关联（Genome-Wide Association, GWA）研究已报道95个调控血清脂质水平的基因座。这些常见变异可解释该类表型约25%的遗传力。截至目前，尚未有针对循环脂质的基因-环境交互作用的无偏筛选研究发表。本研究针对18个欧洲血统人群队列（最大样本量N=32225）的全基因组关联数据开展荟萃分析，旨在筛选可调控已知流行病学危险因素与循环脂质水平之间关联的遗传变异。我们额外纳入8个队列（N=17102）用于验证，结果显示位于4p15区域的rs6448771与腰臀比（WHR）对总胆固醇（TC）的交互作用达到全基因组显著性水平，合并P值为4.79×10⁻⁹。该基因座区域存在两个潜在候选基因：PCDH7与CCKAR，且rs6448771的不同基因型在脂肪组织中呈现差异表达。腰臀比对总胆固醇的效应在携带两份G等位基因的个体中最为显著：该群体腰臀比每相差1个标准差（sd），其总胆固醇浓度即相差0.19个标准差；而在A等位基因纯合子个体中，该差值仅为0.12个标准差。本研究成果可为携带特定基因组特征的人群制定靶向干预策略提供新思路。但未来仍需采用更精准的体脂分布与代谢指标测量方法，以阐明该新发现基因座如何调控二者的联合动态变化。