Computational protocol: Genome-wide Linkage and Regional Association Study of Obesity-related Phenotypes: The GenSalt study

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Protocol publication

[…] The mean or percent of important covariables and obesity-related phenotypes was calculated for all study participants. Multipoint identity by descent estimates were calculated by Merlin software. Multipoint quantitative trait linkage-analyses of adjusted WC and BMI phenotypes were performed using SOLAR software. For the adjustment, each phenotype was regressed on covariates including, age, gender and field center, in a stepwise fashion, and only significant terms (P<0.05) were retained. The residual variance was examined by regressing the square residual from the first regression on the covariates (stepwise) and retaining significant terms. The final adjusted phenotype was computed as the residual from the first regression divided by the square root of the predicted score from the second regression. A final standardization step was taken to ensure a mean of 0 and a standard deviation of 1 for all the adjusted phenotypes.Additive associations between single SNPs located in promising linkage regions (LOD>3) and WC and BMI were assessed using a mixed linear regression model to account for familial correlations. The same covariates used in the linkage analysis, age, gender, and field center, were adjusted in the multivariable analysis. To adjust for multiple comparisons, the raw p-value was adjusted using the FDR method. For SNPs with an FDR Q-value<0.05, we estimated the mean WC and BMI [95% confidence interval (CI)] for each genotype using a mixed linear regression model. The association analysis was conducted using SAS software (version 9.2; SAS Institute Inc.). Pairwise r2 values between significant SNPs in each linkage region were assessed using Haploview software . Finally, because there may be important gender differences in the genetic etiology of obesity-related phenotypes, we conducted additional linkage and association analyses stratified by gender. Due to the limited power of gender-stratified analyses, promising linkage regions for follow-up association study were defined as those with LOD>2. Additional linkage analysis conditional on significant SNPs were performed to determine if there is a lowered LOD score for each respective region. […]

Pipeline specifications

Software tools merlin, Haploview
Application GWAS