Genetic modifiers of body mass index in individuals with cystic fibrosis

To identify modifier loci underlying variation in body mass index (BMI) in persons with cystic fibrosis (pwCF), we performed a genome- wide association study (GWAS). Utilizing longitudinal height and weight data, along with demographic information and covariates from 4,393 pwCF, we calculated AvgBMIz representing the average of per-quarter BMI Z scores. The GWAS incorporated 9.8M single nucle- otide polymorphisms (SNPs) with a minor allele frequency (MAF) > 0.005 extracted from whole-genome sequencing (WGS) of each study subject. We observed genome-wide significant association with a variant in FTO (FaT mass and Obesity-associated gene; rs28567725; p value = 1.21e-08; MAF = 0.41, (3 = 0.106; n = 4,393 individuals) and a variant within ADAMTS5 (A Disintegrin And Met- alloproteinase with ThromboSpondin motifs 5; rs162500; p value = 2.11e-10; MAF = 0.005, (3 =- 0.768; n = 4,085 pancreatic-insuffi- cient individuals). Notably, BMI-associated variants in ADAMTS5 occur on a haplotype that is much more common in African (AFR, MAF = 0.183) than European (EUR, MAF = 0.006) populations (1000 Genomes project). A polygenic risk score (PRS) calculated using 924 SNPs (excluding 17 in FTO) showed significant association with AvgBMIz (p value = 2.2e-16; r(2) = 0.03). Association between var- iants in FTO and the PRS correlation reveals similarities in the genetic architecture of BMI in CF and the general population. Inclusion of Black individuals in whom the single-gene disorder CF is much less common but genomic diversity is greater facilitated detection of as- sociation with variants that are in LD with functional SNPs in ADAMTS5. Our results illustrate the importance of population diversity, particularly when attempting to identify variants that manifest only under certain physiologic conditions.