Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
Obes Facts. 2010 Oct;3(5):294-303. doi: 10.1159/000321537. Epub 2010 Oct 15.
Although heritability of human body weight is assumed to be high, only a small fraction of the variance can as yet be attributed to molecular genetic factors. Single monogenic forms of obesity have been identified. Functionally relevant coding mutations in the melanocortin-4 receptor gene occur in 1-6% of extremely obese children and adolescents and thus represent the most common major gene effect. Genome-wide association studies (GWAS) had previously identified 14 obesity loci with genome-wide significant (p < 5 x 10-8) associations. Many of the respective genes are expressed in the central nervous system. The GIANT (Genetic Investigation of ANtropometric Traits) Consortium has now performed a meta-analysis of GWAS data based on 123,865 individuals of European ancestry followed by confirmatory analyses for the 42 best independent loci in up to 125,931 independent individuals (Speliotes et al: Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics; epub October 2010 [1]). Apart from confirming the 14 known loci, 18 novel BMI-associated loci (p < 5 x 10-8) were identified. Several of the new loci point to genes involved in key hypothalamic pathways of energy balance. The identified variants mostly have small to very small effect sizes; only 1-2% of the BMI variance is explained. Currently, a consensus explanation for this 'missing heritability' in complex diseases has not yet emerged.
虽然人体体重的遗传性被认为很高，但目前只有一小部分可以归因于分子遗传因素。已经确定了一些单基因肥胖形式。在极度肥胖的儿童和青少年中，黑素细胞皮质素-4 受体基因中的功能相关编码突变发生在 1-6%，因此代表最常见的主要基因效应。全基因组关联研究（GWAS）先前已确定了 14 个具有全基因组显著（p < 5 x 10-8）关联的肥胖基因座。各自的基因中有许多在中枢神经系统中表达。GIANT（人类体型遗传研究）联盟现在对基于 123865 名欧洲血统个体的 GWAS 数据进行了荟萃分析，随后对多达 125931 名独立个体中的 42 个最佳独立基因座进行了确认性分析（Speliotes 等人：对 249796 名个体的关联分析揭示了与体重指数相关的 18 个新基因座。自然遗传学；2010 年 10 月在线 [1]）。除了确认 14 个已知基因座外，还确定了 18 个新的 BMI 相关基因座（p < 5 x 10-8）。新基因座中的几个指向涉及能量平衡关键下丘脑途径的基因。已鉴定的变体大多具有小到非常小的效应大小；只有 1-2%的 BMI 差异可以解释。目前，对于复杂疾病中的这种“遗传缺失”，还没有达成共识的解释。
