O4-04-02: a novel susceptibility locus for neurofibrillary tangles at ptprd: evidence of pleiotropic effects on other brain pathologies

Individuals with dementia, including those clinically diagnosed with Alzheimer's Disease (AD), often show mixed pathologies on postmortem examination. We performed independent genome-wide association studies (GWAS) for seven pathologies that influence risk of dementia, and then applied a pleiotropic approach to find variants that have shared effects across multiple pathologies. We investigated 903 brain samples from 2 cohort studies on aging. We began with standard single-trait GWAS for 7 pathology traits: neuritic and diffuse plaques, neurofibrillary tangles, cerebral amyloid angiopathy, micro- and macroscopic infarcts, and Lewy body pathology. Next we assessed a pleiotropic effect by employing an inverted ordinal logistic regression model genome-wide, where alleles are treated as the outcome and traits are treated as independent variables (MultiPhen). In addition, pathway analyses are currently being performed using MAGENTA software in order to identify functionally related genesets that underlay the shared genetic architecture. We report the first susceptibility locus (rs560380) that influences the deposition of neurofibrillary tangles at PTPRD (p=3x10 -8), and replicate this result in an independent dataset (p=0.02 for Braak tangle stages and p=0.01 for CERAD amyloid stages). In addition, we evaluate the possibility that a locus in PTPRD may have an effect on multiple pathologies finding a correlated locus (rs324540, r 2 =0.5) with a pleiotropic p=1.4 x 10 -7, driven by associations with neurofibrillary tangles (p=3.7 x 10 -6), neuritic plaque (p < 0.04). In addition, we find the expected association at APOE (rs429358) with a pleiotropic p-value of 6.3 x 10 -29 driven by associations in 5 of 7 traits. An additional 5 loci were identified with SNPs having pleiotropic p-values < 5x10 -6, driven by 2 to 6 of the traits. For example, the association of the HS3ST4 locus(rs12597858, p=1.8x10 -6) is driven by associations in 6 of the 7 traits (2.8 x 10 -4 < p < 0.05), including all except micro strokes. Results from pathway analyses across the seven traits are currently in progress. We report a novel susceptibility locus for neurofibrillary tangles at PTPRD. The pleiotropic analysis further suggests that looking for shared genetic architecture can identify genetic variants that otherwise would be missed with a univariate approach.