Borecki I B, Bonney G E, Rice T, Bouchard C, Rao D C
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110.
Am J Hum Genet. 1993 Sep;53(3):676-87.
Several recent studies of the body mass index (BMI) have provided support for a recessive major gene influencing heaviness in humans. Segregation analysis of the BMI was carried out recently in a series of randomly sampled French-Canadian families to determine whether we could replicate the major gene finding by using a residual phenotype adjusted for the effects of age and sex. The best model included a recessive major effect for high BMI values with residual familial resemblance; however, Mendelian transmission could not be confirmed, and the no-transmission hypothesis (where all the tau's are constrained to be equal) was not rejected. Considering that the BMI is a complex phenotype affected by many factors and that there are known variations in body composition during growth and aging, we undertook a reanalysis of the data, using a model that allowed the estimation of genotype-specific age and gender effects. New tests on the transmission parameters satisfy the criteria for interfering Mendelian segregation. The results suggest that individuals with the "high" recessive genotype show the greatest degree of heaviness at birth, with a subsequent trend toward lower values throughout life, while individuals with the dominant "normal" genotypes show no appreciable trends with age. In addition, the "high" genotype appears to confer a greater degree of heaviness in females as compared with males. These results, along with other observations from the data, suggest that, while a recessive single gene influence may be discernible, the phenotypic expression of the BMI is likely to be complicated by genotype x environment interactions and, possibly, by the action of other loci. Further, the data also are consistent with the hypothesis that modifying factors may include the adoption of a more prudent life-style by individuals genetically predisposed to heaviness and a secular increase in the incidence, prevalence, and potency of environmentally based triggers leading to a higher penetrance of the "heavy" genotype in the young.
最近几项关于体重指数（BMI）的研究为一种影响人类体重的隐性主基因提供了支持。最近对一系列随机抽样的法裔加拿大家庭进行了BMI的分离分析，以确定我们是否可以通过使用针对年龄和性别影响进行调整的残差表型来重现主基因的发现。最佳模型包括高BMI值的隐性主效应以及残差家族相似性；然而，孟德尔遗传传递无法得到证实，并且非传递假设（所有τ值都被约束为相等）也未被拒绝。考虑到BMI是一个受多种因素影响的复杂表型，并且在生长和衰老过程中身体组成存在已知的变化，我们使用一个允许估计基因型特异性年龄和性别效应的模型对数据进行了重新分析。对传递参数的新测试满足干扰孟德尔分离的标准。结果表明，具有“高”隐性基因型的个体在出生时体重最重，随后在一生中呈现下降趋势，而具有显性“正常”基因型的个体则没有明显的年龄趋势。此外，与男性相比，“高”基因型在女性中似乎导致更重的体重。这些结果以及数据中的其他观察结果表明，虽然可能可以识别出隐性单基因的影响，但BMI的表型表达可能会因基因型与环境的相互作用以及可能的其他基因座的作用而变得复杂。此外，数据也与以下假设一致，即修饰因素可能包括遗传上易胖的个体采用更谨慎的生活方式，以及基于环境的触发因素的发生率、患病率和效力的长期增加，导致“肥胖”基因型在年轻人中的更高外显率。
