Fine-mapping in African Americans of 8 recently discovered genetic loci for plasma lipids: the Jackson Heart Study.
Fine-mapping in African Americans of 8 recently discovered genetic loci for plasma lipids: the Jackson Heart Study.
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DOI：
10.1161/circgenetics.109.914267
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发表时间：
2010-08
期刊：
影响因子：
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通讯作者：
Kathiresan S
中科院分区：
文献类型：
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作者：
Keebler ME;Deo RC;Surti A;Konieczkowski D;Guiducci C;Burtt N;Buxbaum SG;Sarpong DF;Steffes MW;Wilson JG;Taylor HA;Kathiresan S
在欧洲血统人群中进行的全基因组关联研究已经确定了与脂质相关的新基因组区域，但它们与非裔美国人的相关性尚不清楚。在基于社区的4605名非裔美国人队列Jackson心脏研究中，我们对8个新的脂质位点中的8个指数snp和488个标记snp进行了基因分型。对于每个性状，我们计算了年龄、性别和全球血统调整后的残差，并进行了多变量线性回归，以检测基因型-表型与本地血统调整的相关性。为了探索混合效应，我们对每个基因座上有2个非洲祖先等位基因或至少1个欧洲等位基因的个体进行了分层分析。我们确认了2个指数snp与非裔美国人的脂质性状有关，另外3个有暗示的关联。然而，与非洲本地祖先亚组相比，5个相关snp中有4个的效应量在欧洲本地祖先亚组中更大，这表明复制是由欧洲血统片段驱动的。通过精细定位，我们发现了3个具有显著相关性的新snp，其中两个对祖先群体的甘油三酯水平具有一致的影响：DOCK7/ANGPTL3附近的rs636523和GCKR中的rs780093。非洲LD模式无助于缩小关联信号。我们证实了与欧洲血统人群中脂质性状相关的5个遗传区域与非裔美国人相关。为了进一步评估这些基因座，需要在更大的非裔美国人队列中进行精细定位和/或重测序。
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear. We genotyped 8 index SNPs and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared to the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, two with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African LD patterns did not assist in narrowing association signals. We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.