Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
Nephrology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Diabetes. 2021 Apr;70(4):986-995. doi: 10.2337/db20-0158. Epub 2021 Jan 7.
Genome-wide association studies (GWAS) and linkage studies have had limited success in identifying genome-wide significantly linked regions or risk loci for diabetic nephropathy (DN) 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 >6,000 individuals with T1D and their relatives without diabetes. We performed a linkage study for 177 pedigrees consisting of 452 individuals with T1D and their relatives using a genome-wide genotyping array with >300,000 single nucleotide polymorphisms and PSEUDOMARKER software. Analysis resulted in genome-wide significant linkage peaks on eight chromosomal regions from five chromosomes (logarithm of odds score >3.3). The highest peak was localized at the HLA region on chromosome 6p, but whether the peak originated from T1D or DN remained ambiguous. Of other significant peaks, the chromosome 4p22 region was localized on top of , a gene associated with focal segmental glomerulosclerosis, suggesting this gene may play a role in DN as well. Furthermore, rare variants have been associated with DN and chronic kidney disease near the 4q25 peak, localized on top of .
全基因组关联研究(GWAS)和连锁研究在确定 1 型糖尿病(T1D)个体的全基因组显著连锁区域或风险基因座方面取得了有限的成功。随着 GWAS 队列的扩大,它们还包括了更多有记录和无记录的家族关系。在这里,我们在一个超过 6000 名 T1D 患者及其无糖尿病亲属的研究队列中进行了计算推断和手动谱系构建。我们使用包含超过 300000 个单核苷酸多态性的全基因组基因分型阵列和 PSEUDOMARKER 软件对由 452 名 T1D 患者及其亲属组成的 177 个家系进行了连锁研究。分析导致了五个染色体上的八个染色体区域的全基因组显著连锁峰(对数优势评分>3.3)。最高的峰定位于染色体 6p 的 HLA 区域,但该峰是否来自 T1D 或 DN 仍不清楚。在其他显著峰中,染色体 4p22 区域定位于 基因的顶部,该基因与局灶节段性肾小球硬化症有关,这表明该基因也可能在 DN 中发挥作用。此外,在 4q25 峰附近的慢性肾病和 DN 与罕见变异有关,该峰定位于 基因的顶部。