A pilot study of whole exome sequencing in progressive supranuclear palsy

Objective: To identify genetic variants associated with Progressive Supranuclear Palsy (PSP) using whole exome sequencing.

Background: PSP is a rare tauopathy but is the second most common cause of degenerative parkinsonism, after Parkinson’s diseases. Clinically, PSP is characterized by falls, axial rigidity, vertical supranuclear gaze palsy. Genetically, Mendelian familial transmission is not commonly seen. The H1 Haplotype, including MAPT gene region, had been shown to confer risk in PSP. Previous GWAS showed significant association in a few loci including MAPT. There has been little data on the rare variants associated with PSP. This study aims at identifying potential rare variants in conferring risk to PSP.

Methods: DNA was extracted from the brain of 104 cases of pathologically confirmed PSP cases. Whole exome sequencing of these samples were performed using Illumina Truseq Capture in Illumina HiSeq platform. Sequencing data was aligned with BWA; duplicates marked and sorted with Picard; variant calling was done according to the best practices suggested by GATK, using HaplotypeCaller. Functional annotation was carried out with Annovar. To compare with PSP, Control Exome data was obtained from the IPDGC.

Results: Only 87 PSP cases remained after the quality control measures and were used to compare with over four hundred controls from the IPDGC exome control data. There were cluster of significantly associated variants around the MAPT or H1/H2 haplotype region, reconfirming the previous known association of H1 with PSP. No significant novel variants were found in the MAPT. Other uncommon or rare variants across the exome did not reach genome-wide significant given the small number of cases in this preliminary study.

Conclusions: 1) H1 /H2 haplotype was associated with PSP. 2) the overall non-statistically significant result may be due to a) the small sample size making it difficult to achieve genomewide association; b) the pathological variants may be very rare, and at multiple loci; c) the controls were not age matched; d) the pathological variants may not be coding variant, e.g. expression quantitative trait variant. 3) Future metaanalysis may be need to increase the sample size and whole genome study may be need to study the non-coding region.