Conclusion
We have identified several non-synonymous variants across neighboring genes of MAPT that may warrant further genetic and functional investigation within the biological etiology of PD.
Methods
Sanger sequencing of coding exons in 90 Caucasian late-onset PD (LOPD) patients was performed. Specific gene sequencing for LRRC37A, LRRC37A2, ARL17A and ARL17B was not possible given the high homology, presence of pseudogenes and copy number variants that are in the region, and therefore four genes (NSF, KANSL1, SPPL2C, and CRHR1) were included in the analysis. Coding variants from these four genes that did not perfectly tag (r2 = 1) the MAPT H1/H2 haplotype were genotyped in an independent replication series of Caucasian PD cases (N = 851) and controls (N = 730).
Results
In the 90 LOPD cases we identified 30 coding variants. Eleven non-synonymous variants tagged the MAPT H1/H2 haplotype, including two SPPL2C variants (rs12185233 and rs12373123) that had high pathogenic combined annotation dependent depletion (CADD) scores of >20. In the replication series, the non-synonymous KANSL1 rs17585974 variant was in very strong LD with MAPT H1/H2 and had a high CADD score of 24.7.