A study of linkage and association of body mass index in the Old Order Amish.

Obesity is thought to have a genetic component with the estimates of heritability ranging from 0.25-0.40. As part of an ongoing study of obesity in the Old Order Amish, seven two- and three-generation families (157 individuals) were assessed for 21 traits related to obesity, including body mass index (BMI) and BMI-percentile (a standardized distribution of BMI adjusted for age and sex). Genotyping was performed using a panel of 384 short-tandem repeat markers. In this sample, the estimates of heritability ranged from 0.16-0.31 for BMI and from 0.40-0.52 for BMI-percentile. Model-independent linkage analysis identified candidate regions on chromosomes 1, 5, 7, 8, and 11. Given that several markers on 7q were significant for both BMI and BMI-percentile (P < or = 0.001) and that the structural locus for leptin was located on 7q, this region was considered to be the primary candidate region. Subsequent typing of additional flanking markers on 7q corroborated the original findings. Tests of intrafamilial association for alleles at markers in this candidate region were significant at similar levels. Although there is some evidence for linkage and association in the region containing leptin, there appears to be stronger evidence for linkage (P < or = 0.001) and association (P < or = 0.00001) with BMI in a region 10-15 cM further downstream of leptin, flanked by markers D7S1804 and D7S3070 with peak values from D7S495-D7S1798. Evidence from linkage and association studies suggests that this region (D7S1804-D7S3070) may be responsible, at least in part, for variation in BMI and BMI-percentile in the Old Order Amish.

Comparison of variance components, ANOVA and regression of offspring on midparent (ROMP) methods for SNP markers.

An extension of the traditional regression of offspring on midparent (ROMP) method was used to estimate the heritability of the trait, test for marker association, and estimate the heritability attributable to a marker locus. The fifty replicates of the Genetic Analysis Workshop (GAW) 12 simulated general population data were used to compare the ROMP method with the variance components method as implemented in SOLAR as a test for marker association, and to a standard analysis of variance (ANOVA) method. Large sample statistical properties of the ROMP and ANOVA methods were compared using 2,000 replicates resampled from the families of the original 50 replicates. Overall, the power to detect a completely associated single nucleotide polymorphism (SNP) marker was high, and the type I error rates were similar to nominal significance levels for all three methods. The standard deviations of the estimates of the heritability of the trait were large for both SOLAR and ROMP, but the estimates were, on average, close to those of the generating model for both methods. However, on average, SOLAR overestimated the heritability attributable to the associated SNP marker (by 256%) while ROMP underestimated it (by 26%).