Muscling in on the genetics of quantitative disease traits.

OUR COMPREHENSION of how genetic factors influence a person’s susceptibility to complex disease has evolved markedly during the past 20 years. Major advances in molecular genetics technologies have contributed greatly to this process, as have improvements in phenotyping methods and statistical algorithms used in the analysis of quantitative genetics data. Although genetics studies that focus on discrete disease outcomes are valuable, they are uninformative of the disease’s etiology. One important etiological trait for a variety of health disorders is muscle wasting (sarcopenia), which frequently occurs as a consequence of aging, certain diseases, and limb immobilization following orthopedic injury. Studies that seek to disentangle the genetic from the environmental influences on muscle mass phenotypes are important as they may eventually contribute to the prevention or treatment of sarcopenia-related disorders. This invited editorial focuses on a study from the Journal of Applied Physiology by Prior et al. (11) that addresses this issue in eight large, multigenerational families from the Caribbean island of Tobago. Using advanced phenotyping and statistical analysis methods, the authors established that the heritability of lean soft-tissue mass and muscle crosssectional area in this population is roughly 20%. The authors also found that the heritability of limb-specific muscle development may vary by sex and age and that cigarette smoking, parity, and oral contraceptive use may be important environmental determinants of skeletal muscle morphology. Skeletal muscle plays important roles in the metabolism of energy substrates, the generation of hormones required for a range of physiological processes including cell repair and signaling, and the maintenance of functional capacity and mobility. Muscle wasting (sarcopenia) frequently occurs as a consequence of aging, diseases such as anorexia nervosa, AIDS, and cancer, and limb immobilization following orthopedic injury. The consequences of sarcopenia include a decline in bone mineral density and functional capacity, and increased susceptibility to fracture, insulin resistance and dyslipidemia (1, 9, 12). Resistance exercise training is effective at delaying age-related sarcopenia and in regenerating muscle tissue following disease or injury. However, the molecular mechanisms that underlie the processes of sarcopenia and muscle regeneration are poorly understood, and safe and effective pharmacotherapy for either scenario is lacking (7). Muscle morphology phenotypes include muscle mass, crosssectional area, regeneration rates, and sarcopenia. Studies characterizing the heritability of these phenotypes in people from different ethnic or environmental backgrounds may yield information pointing toward the factors underlying the betweenindividual variation in these traits. Despite known differences in muscle morphology between ethnic groups (2), little emphasis has been placed on determining the genetic factors that underlie these differences; most heritability studies related to this topic have focused on populations of European ancestry and have used relatively imprecise anthropometric measures. Prior and colleagues (11) describe the heritability of muscle morphology phenotypes in eight large, multigenerational families from the Caribbean island of Tobago. The study is unique in that it is the first to assess the heritability of muscle phenotypes using objective methods (dual-energy X-ray absorptiometry and computerized tomography) in extended families of recent African descent. Furthermore, the study design permitted Prior et al. (11) to partially assess the effect-modifying roles of age and sex on the heritability of muscle phenotypes. The authors conclude that lean soft-tissue mass and muscle cross-sectional area are modestly heritable traits (h 0.20) and that the heritability of limb-specific muscle development may vary by sex and age. The authors also conclude that cigarette smoking, parity, and oral contraceptive use may be important environmental determinants of skeletal muscle morphology. A common misconception is that estimates of “heritability” and “genetics” are always synonymous. Because nongenetic environmental factors are often shared to a greater extent by family members than nonmembers, it is possible for a phenotype to segregate within a family in the absence of a genetic cause. One example of this is physical activity levels in children, where the influence of familial environmental factors can constrict the genetic influences on activity levels (5). A second example is adult obesity. Men and women “selectively mate,” whereby obese individuals tend to select obese partners (10). The nongenetic segregation of obesity within families can also emerge during the course of a relationship independently of mate selection; in a recently reported prospective study, people whose spouses were initially nonobese, but who subsequently became obese, were themselves at greater risk of becoming obese, seemingly because obesogenic environmental factors are shared and evolve more within than between close social networks such as families (3). The same may also be true of muscle morphology traits. Thus conventional approaches to assess heritability using collections of families, where the trait correlation within sets of highly genetically related individuals is compared with the trait correlation in sets of less genetically related individuals, can be prone to confounding, primarily because simple heritability estimates (h) incorporate both genetic and shared-environmental factors. Thus, if h is interpreted solely as the variance explained by “genetic” factors, then the role that genetic variation plays in the development of the trait may be overestimated. To circumvent this limitation in family studies requires sophisticated designs and analytical methods that partition out the genetic from the sharedand unshared-environmental variances. In twin studies, providing zygosity is accurately determined, the genetic similarity of participants is known (for monozygotic Address for reprint requests and other correspondence: P. W. Franks, Genetic Epidemiology and Clinical Research Group, Dept. of Public Health and Clinical Medicine, Division of Medicine, Umeå Univ. Hospital, Umeå 901 87, Sweden (e-mail: [email protected]). J Appl Physiol 103: 1111–1112, 2007; doi:10.1152/japplphysiol.00827.2007.