鉴定 2 型糖尿病、出生体重及其多效性位点的新型变异。
Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci.
机构信息
Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Department of Endocrinology and Metabolism, Affiliated Nanhai Hospital of Southern Medical University, Guangzhou, China.
出版信息
J Diabetes. 2017 Oct;9(10):898-907. doi: 10.1111/1753-0407.12510. Epub 2017 Jan 20.
BACKGROUND
Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms (SNPs) in T2D and birth weight, and their pleiotropic loci.
METHODS
A pleiotropy-informed conditional false discovery rate (cFDR) method was applied to two independent genome-wide association studies (GWAS) summary statistics of T2D (n = 149 821) and birth weight (n = 26 836).
RESULTS
A conditional Q-Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of cFDR < 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (cFDR < 0.05) were identified. Conjunctional cFDR (ccFDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (ccFDR < 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1; rs1012635; cFDR < 0.05) and adenylate cyclase 5 (ADCY5; rs4677887; cFDR < 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the "fetal insulin hypothesis."
CONCLUSION
Several pleiotropic loci were identified between T2D and birth weight by leveraging GWAS results. The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and birth weight.
背景
临床和流行病学研究结果表明，2 型糖尿病（T2D）与低出生体重之间存在关联。然而，两者之间的关系本质尚不清楚。本研究旨在鉴定 T2D 和出生体重的新的单核苷酸多态性（SNP）及其多效性位点。
方法
应用多效性信息条件假发现率（cFDR）方法，对两项独立的 T2D（n=149821）和出生体重（n=26836）全基因组关联研究（GWAS）汇总统计数据进行分析。
结果
条件 Q-Q 图显示，在不同水平上与出生体重相关的 T2D 遗传变异显著富集。鉴定出 133 个 T2D 相关 SNP，包括 120 个新的 SNP，其显著性阈值为 cFDR<0.05；鉴定出 13 个与出生体重相关的显著 SNP，包括 12 个新的 SNP（cFDR<0.05）。联合 cFDR（ccFDR）分析确定了 9 个 T2D 和出生体重共有的多效性位点，包括 7 个新的位点（ccFDR<0.05）。两个新的 SNP 位于细胞周期蛋白依赖性激酶 5 调节亚基相关蛋白 1 样 1（CDKAL1；rs1012635；cFDR<0.05）和腺苷酸环化酶 5（ADCY5；rs4677887；cFDR<0.05）基因，值得注意。这两个基因通过“胎儿胰岛素假说”途径增加了 T2D 和低出生体重的风险。
结论
通过利用 GWAS 结果，鉴定出 T2D 和出生体重之间的多个多效性位点。研究结果使我们有可能解释更多的表型遗传率，并加深我们对 T2D 和出生体重之间共享病理生理学的理解。
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