Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease.
2017
Abstract Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent
assessmentsof
learningand memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and
Trail Making Test[TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton
Judgmentof
Line Orientation[JoLO]), and global cognitive function (
Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel
association test. The significance threshold was defined as a
false discovery rate-corrected p -value ( P FDR ) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the
cognitive tests. These included GBA rs2230288 (E326K; P FDR = 2.7 × 10 −4 ) for JoLO, PARP4 rs9318600 ( P FDR = 0.006), and rs9581094 ( P FDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 ( P FDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.
Keywords:
- Cognitive test
- Psychology
- Verbal fluency test
- Developmental psychology
- Genetic analysis
- Trail Making Test
- Montreal Cognitive Assessment
- Cognitive psychology
- Recall
- Cognition
- Judgment of Line Orientation
- Internal medicine
- Effects of sleep deprivation on cognitive performance
- Clinical psychology
- verbal learning
- Endocrinology
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