Abstract

Genome-wide association studies (GWAS) and linkage studies have had only limited success in discovering genome-wide significantly linked regions or risk loci for diabetic nephropathy in individuals with type 1 diabetes (T1D). As GWAS cohorts have grown, they have also included more documented and undocumented familial relationships. Here, we computationally inferred and manually curated pedigrees in a study cohort of more than 6,000 individuals with T1D and their non-diabetic relatives. We performed linkage study for 177 pedigrees consisting of 452 individuals with T1D and their relatives using a genome- wide genotyping array with more than 300,000 SNPs and the PSEUDOMARKER software. The analysis resulted in genome-wide significant linkage peaks on eight chromosomal regions from five chromosomes (logarithm of odds [LOD]>3.3). The highest peak was localized at the HLA region on chromosome 6p, but whether the peak originates from T1D or diabetic nephropathy, remains ambiguous. Of the other significant peaks, the chromosome 4p22 region is localized on top of a gene associated with focal segmental glomerulosclerosis, ARHGAP24, suggesting that the gene may play a role in diabetic nephropathy as well. Furthermore, rare variants have been associated with diabetic nephropathy and chronic kidney disease near the 4q25 peak, localized on top of CCSER1.