Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
BMC Med Genomics. 2011 Jun 28;4:51. doi: 10.1186/1755-8794-4-51.
Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.
We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index>40 kg/m2) and 163 Swedish subjects (>45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P<0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n=4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.
Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830G and BDNF rs988712G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830G with P=2.82×10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712G with P=5.2×10(-17) and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P=0.0001) and fat cell (P=0.04) expression of KCNMA1 was increased in obesity.
We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
最近的全基因组关联（GWA）分析已经确定了与肥胖相关的常见单核苷酸多态性（SNP）。然而，报告的肥胖遗传变异仅解释了人群中预期存在的总遗传变异的一小部分。因此，许多控制肥胖的遗传变异仍有待确定。本研究旨在使用 GWA 结合多步逐步验证来鉴定与肥胖相关的其他基因。
我们对 164 名病态肥胖受试者（BMI：体重指数>40kg/m2）和 163 名瑞典受试者（>45 岁）进行了 GWA 分析，这些受试者一直保持消瘦。在第二组中，对与 GWA 中肥胖相关性最强的 700 个 SNP 进行了分析，该组包括 460 名病态肥胖受试者和 247 名瑞典成年人。23 个 SNP 仍然与肥胖显著相关（名义 P<0.05），并以逐步方式在瑞典、法国和德国的五个额外队列中进行了跟踪，这些队列共包括 4214 名肥胖者和 5417 名瘦或基于人群的对照个体。三个样本，n=4133，用于研究与 BMI 的基于人群的关联。对 14 名成年人腹部皮下脂肪组织中与肥胖相关的基因表达进行了研究。
钾通道，钙激活，大电导，亚家族 M，alpha 成员（KCNMA1）rs2116830G 和脑源性神经营养因子（BDNF）rs988712G 在六个被研究的病例对照队列中的五个队列中与肥胖相关。在对 4838 名肥胖者和 5827 名对照者的荟萃分析中，我们获得了 KCNMA1 rs2116830G 与肥胖的全基因组显著等位基因关联，P=2.82×10(-10)，病例与对照的比值比（OR）为 1.26[95%置信区间（CI）为 1.12-1.41]，BDNF rs988712G 的 P=5.2×10(-17)，OR 为 1.36[95%CI 为 1.20-1.55]。KCNMA1 rs2116830*G 与基于人群的样本中的 BMI 无关。脂肪组织（P=0.0001）和脂肪细胞（P=0.04）中 KCNMA1 的表达增加了肥胖。
我们已经确定 KCNMA1 是肥胖的一个新的易感基因座，并在全基因组显著水平上证实了 BDNF 基因座的关联。
