Coding-sequence variants are associated with blood lipid levels in 14,473 Chinese
Coding-sequence variants are associated with blood lipid levels in 14,473 Chinese
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编码序列变异与 14,473 名中国人的血脂水平相关
DOI：
10.1093/hmg/ddw261
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Dongfeng Gu
中科院分区：
文献类型：
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作者：
Xiangfeng Lu;Jun Li;Huaixing Li;Yang Chen;Laiyuan Wang;Meian He;Yiqin Wang;Liang Sun;Yao Hu;Jianfeng Huang;Feijie Wang;Xuezhen Liu;Shufeng Chen;Kuai Yu;Xueli Yang;Zengnan Mo;Xu Lin;Tangchun Wu;Dongfeng Gu
以前发现的常见变异只解释了一小部分性状遗传力，在大多数位点上，潜在的致病基因及其功能变异的身份仍然未知。为了确定影响血脂水平的低频和罕见编码变异，我们对14，473名中国受试者的全外显子组关联研究进行了荟萃分析，然后对来自6，534个样本的1000个基因组进行了联合分析。我们复制了24个先前报道的具有全外显子组显著性（P < 3.3 × 10 − 7）的脂质位点，包括10个已确认的脂质位点的14个编码变体（P范围为1.44 × 10 − 7至1.64 × 10 − 45）。其中，6种编码变异显示出人群特异性关联，并且与先前在欧洲人群中发现的关联无关，包括4种低频（PCSK 9 p.Arg93Cys、HMGCR p.Tyr311Ser、APOA 5 p.Gly185Cys和CETP p.Asp399Gly）和2种常见变异（APOB p.Arg532Trp和APOA 4 p.Ser147Asn）。此外，我们还在中国人中发现了三种新的LPA、LIPC和LDLR非编码区变异。PCSK 9、HMGCR、LPA、APOA 5和LDLR的独立变异也与预期方向的冠状动脉疾病风险增加相关。在基于基因的测试中，PCSK9、HMGCR和CEPT中罕见或低频变异的负担与血脂水平有很强的相关性（P < 2.8 × 10 − 6）。我们的研究结果确定了额外的人群特异性可能的因果变异。我们的数据表明，编码变体的等位基因频率的种族间差异可能导致不同种族群体之间的不同关联信号，突出了包括不同人群以揭示与血脂水平相关的遗传变异的重要性。
Previously identified common variants explain only a small fraction of the trait heritability and at most loci the identities of the underlying causal genes and their functional variants still remain unknown. To identify the low-frequency and rare coding variants that influence lipid levels, we conducted a meta-analysis of exome-wide association studies in 14,473 Chinese subjects, followed by a joint analysis with 1000 genomes imputed data from 6,534 samples. We replicated 24 previously reported lipid loci with exome-wide significance (P < 3.3 × 10 − 7), including fourteen coding variants at ten confirmed lipid loci (P range from 1.44 × 10 − 7 to 1.64 × 10 − 45). Of these, six coding variants showed population-specific associations and were independent of previously identified associations in European populations, including four low-frequency (PCSK9 p.Arg93Cys, HMGCR p.Tyr311Ser, APOA5 p.Gly185Cys and CETP p.Asp399Gly) and two common (APOB p.Arg532Trp and APOA4 p.Ser147Asn) variants. Furthermore, we detected three new lead non-coding variants at LPA, LIPC and LDLR in Chinese. The independent variants at PCSK9, HMGCR, LPA, APOA5 and LDLR were also associated with increased risk of coronary artery disease in the expected direction. In gene-based tests, the burden of rare or low frequency variants in PCSK9, HMGCR and CEPT exhibited strong associations with blood lipid levels (P < 2.8 × 10 − 6). Our findings identify additional population-specific possible causal variants. Our data demonstrate that the inter-ethnic differences in allele frequencies of coding variants may lead to different association signals across ethnic groups, highlighting the importance of including diverse populations to uncover genetic variation associated with lipid levels.