A novel association of rs13334070 in the RPGRIP1L gene with adiposity factors discovered by joint linkage and linkage disequilibrium analysis in Iranian pedigrees: Tehran Cardiometabolic Genetic Study (TCGS)

Abstract

Understanding the genetic and metabolic bases of obesity is helpful in planning and developing health strategies. Therefore, the first family‐based joint linkage and linkage disequilibrium study was conducted in Iranian pedigrees to assess the relationship between obesity and single‐nucleotide polymorphisms (SNPs) located in the 16q12.2 region. In the present study, a total of 13,344 individuals were included, of whom 12,502 individuals were within 3,109 pedigrees and 842 were unrelated singletons. To investigate the relationship between obesity and genetic variants, a joint model of linkage and linkage disequilibrium was applied. Moreover, a sequence kernel association test (SKAT) was used to evaluate the association of the SNP set with body size and lipid profile measurements. The joint model showed that rs13334070, in the intron 4 of the RPGRIP1L gene, has a significant association with obesity. According to the 4‐gamete rule, which is a procedure for constructing SNP sets by considering recombination occurrence between SNPs, this polymorphism has a high correlation with six nearby SNPs that make an SNP set. SKAT showed that this SNP set has a significant association with body size factors, but almost no association with most of the lipid profile measurements. In conclusion, from the result of this study, it might be reasonable to consider RPGRIP1L as an important gene whose variations could be associated with obesity risk factors.

Kernel machine SNP set analysis finds the association of BUD13, ZPR1, and APOA5 variants with metabolic syndrome in Tehran Cardio-metabolic Genetics Study

“…To increase the association test's power and accommodate the epistasis effect between adjacent correlated SNPs in a set, we used a logistic kernel machine regression method to assess SNP sets' association binary phenotype 23 , 28 , 49 , 50 . In the additive model, genotypes AA, Aa, and aa recoded to 0, 1, and 2, respectively 28 , 50 .…”

Title: Cohort profile update: Tehran Cardiometabolic Genetic Study, a path toward precision medicine

“…As the rst comprehensive study on Iranian pedigrees, we conducted a family-based joint linkage and linkage disequilibrium analysis of 3109 pedigrees. We found that RPGRIP1L is the key gene within the 16q12.2 region whose polymorphisms could be associated with obesity risk factors among TCGS participants [24]. Moreover, different SNP clusters composed of rare and common SNPs within the 16q12.2 region signi cantly increased BMI among Iranians.…”

Case Report: Novel RPGRIP1L Gene Mutations Identified by Whole Exome Sequencing in a Patient With Multiple Primary Tumors

“…Recently, mutations in RPGRIP1L were reported in obesity and brain function. One study showed that rs13334070, in RPGRIP1L intron 4, has a significant association with obesity (Javanrouh et al, 2019). Reble et al recently identified a SNV, rs7203525, that influences an alternative splicing event in RPGRIP1L, increasing exon 20 inclusion and potentially impacting brain function (Reble et al, 2020).…”