Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases

Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.MethodsWe conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.ResultsWe identified 5 associated loci at a genome-wide significance threshold P < 5 × 10− 8, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10− 6). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson’s disease and amyotrophic lateral sclerosis.ConclusionsIn total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0270-8) contains supplementary material, which is available to authorized users.

Genome‐wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy

“…BBBIPPS used the same NNIPPS diagnostic criteria and was conducted in the same study centers in France. These patients were previously included as a subset of a GWAS in PSP that we had published …”

“…NNIPPS and BBBIPPS recruited a well‐characterized cohort of patients with PSP. This cohort was also included in our previously reported joint‐analysis GWAS of PSP . Here, we performed genome‐wide association on this cohort alone to confirm genetic loci implicated in PSP and validate this clinical PSP cohort, comparing with previous GWASs.…”

“…Variation in the gene encoding tau, MAPT , has been established as a genetic risk factor for PSP . Genome‐wide association studies (GWASs) have also identified variants in MOBP , STX6 , and other genes as significant risk factors . Although further studies have found trends toward association, they have been underpowered, and these associations have not been definitively reproduced in an independent sample.…”

One decade ago, one decade ahead in progressive supranuclear palsy

“…The first study selected specific SNPs from the Höglinger GWAS and reassessed them in a cohort combining the original population and new definite PSP cases and controls . The second study combined the definite cases of the Höglinger GWAS with new cases with clinical PSP diagnosis and utilized a genotype imputation methodology . Both studies also reported new associations, the first with a nonsynonymous SNP in the SLCO1A2 gene and an intergenic SNP near DUSP10 , and the second study with an intronic SNP in the SLCO1A2 gene and an SNP associated with the RUNX2 gene.…”

“…Both studies also reported new associations, the first with a nonsynonymous SNP in the SLCO1A2 gene and an intergenic SNP near DUSP10 , and the second study with an intronic SNP in the SLCO1A2 gene and an SNP associated with the RUNX2 gene. All the studies mentioned above have confirmed the contribution of the H1 haplotype in the risk of PSP and some have identified additional SNPs in the MAPT locus that independently influence this risk . Using a different approach, Jabbari and colleagues conducted a GWAS with genotype imputation comparing cases with RS versus cases with PSP‐P and PSP‐PGF.…”