Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

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 1,105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and 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 Judgment of 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 (PFDR) 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; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006) and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 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.

Multivariate prediction of dementia in Parkinson’s disease

“…Consistent with our previous cross-sectional reports 26 , 27 , we also found no association between the MAPT H1 haplotype and specific cognitive test performance, dementia diagnosis, or cognitive decline during follow-up. Previous reports on MAPT and cognition are mixed, with one group reporting faster decline in MMSE scores and greater dementia risk in PD patients with the H1 haplotype 28 and another showing a greater association between the H1 haplotype and PD diagnosis among those with dementia 29 .…”

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

“…Specifically, heterozygous GBA mutated-PD patients showed an increased disease risk, earlier age at onset, and faster progression. In addition to cognitive decline, alterations in executive functions and language processing were observed in patients carrying this genetic alteration [40,41]. Alterations in the lysosomal pathways have been widely described in sporadic and genetic FTD [42,43,44,45].…”

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

“…Genetic variants in APOE and MAPT have time-dependent effects on cognition, which vary with disease stage: MAPT appears to have its greatest impact on cognitive decline in early PD, whereas APOE may have a more pronounced effect late in the course of the disease (Collins and Williams-Gray, 2016 ). A recent GWAS on an extensive neuropsychological battery in PD patients failed to replicate prior associations with APOE, MAPT, catechol-O-methyltransferase (COMT) , or SNCA (Mata et al, 2017 ). In cross-sectional studies, the prevalence of dementia in GBA -PD cases is about 50%, compared to 24–31% in idiopathic PD cases (Setó-Salvia et al, 2012 ).…”