Genome-wide analysis of epistasis in body mass index using multiple human populations.
Genome-wide analysis of epistasis in body mass index using multiple human populations.
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DOI：
10.1038/ejhg.2012.17
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发表时间：
2012-08
期刊：
影响因子：
--
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中科院分区：
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我们通过详尽的成对基因组扫描调查了四个欧洲人群（n<1200）中人体体重指数（BMI）的基因-基因相互作用（上位性），其中通过测试线性回归模型拟合两个单核苷酸多态性（SNP）与没有相互作用的SNP，将相互作用计算为F比。在关联性测试之前，BMI被校正了性别和年龄，标准化并调整了相关性。根据一致阈值（P=5.0E−08）和Bonferroni校正阈值（P=1.1E−12），单个SNP和SNP相互作用在任一队列中均不具有全基因组显著性。接下来，我们比较了跨队列的亚基因组显著SNP相互作用（P<5.0E-08），以识别常见的上位性信号，其中SNP被注释到基因中以测试基因本体（GO）富集。在对通常富集的GO术语有贡献的上位基因中，19个在研究队列中共有，其中15个是先前发表的全基因组关联基因座，包括与身高相关的CDH 13（钙粘蛋白13）和与循环胰岛素样生长因子1和结合蛋白3相关的SORCS 2（分拣蛋白相关的VPS 10结构域受体2）。跨队列测试了19个共享上位基因与涉及BMI候选位点的基因（P<5.0E-08）之间的相互作用，发现至少在一个队列中有8个在SNP水平上复制（P<0.05），进一步测试显示在单独的欧洲人群中复制有限（n>5000）。我们的结论是，在多个人群中的上位性的全基因组分析是一种有效的方法，提供新的见解的遗传调控的BMI，但需要额外的努力来确认的结果。
We surveyed gene–gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E−08) and a Bonferroni corrected threshold (P=1.1E−12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E−08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E−08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
6.5
作者：
Kimmel AR;Brasaemle DL;McAndrews-Hill M;Sztalryd C;Londos C
通讯作者：
Londos C
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Akula N;Baranova A;Seto D;Solka J;Nalls MA;Singleton A;Ferrucci L;Tanaka T;Bandinelli S;Cho YS;Kim YJ;Lee JY;Han BG;Bipolar Disorder Genome Study (BiGS) Consortium;Wellcome Trust Case-Control Consortium;McMahon FJ
通讯作者：
McMahon FJ
影响因子：
1.9
作者：
Polasek, Ozren;Marusic, Ana;Rudan, Igor
通讯作者：
Rudan, Igor