. 2017 Aug:56:211.e1-211.e7.

doi: 10.1016/j.neurobiolaging.2017.04.009. Epub 2017 Apr 20.

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

Ignacio F Mata¹, Catherine O Johnson², James B Leverenz³, Daniel Weintraub⁴, John Q Trojanowski⁵, Vivianna M Van Deerlin⁶, Beate Ritz⁷, Rebecca Rausch⁸, Stewart A Factor⁹, Cathy Wood-Siverio⁹, Joseph F Quinn¹⁰, Kathryn A Chung¹⁰, Amie L Peterson-Hiller¹⁰, Alberto J Espay¹¹, Fredy J Revilla¹², Johnna Devoto¹¹, Dora Yearout¹, Shu-Ching Hu¹, Brenna A Cholerton¹³, Thomas J Montine¹⁴, Karen L Edwards², Cyrus P Zabetian¹⁵

Affiliations

¹ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
² Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA, USA.
³ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Portland Veterans Affairs Medical Center, Portland, OR, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
¹¹ Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA.
¹² Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA.
¹³ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁵ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: zabetian@u.washington.edu.

PMID: 28526295
PMCID: PMC5536182
DOI: 10.1016/j.neurobiolaging.2017.04.009

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

Ignacio F Mata et al. Neurobiol Aging. 2017 Aug.

. 2017 Aug:56:211.e1-211.e7.

doi: 10.1016/j.neurobiolaging.2017.04.009. Epub 2017 Apr 20.

Authors

Affiliations

¹ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
² Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA, USA.
³ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Portland Veterans Affairs Medical Center, Portland, OR, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
¹¹ Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA.
¹² Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA.
¹³ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁵ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: zabetian@u.washington.edu.

PMID: 28526295
PMCID: PMC5536182
DOI: 10.1016/j.neurobiolaging.2017.04.009

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 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 (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 impairment; Genetics; NeuroX; Parkinson's disease.

Published by Elsevier Inc.

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Conflict of interest statement

Financial Disclosure/Conflict of Interest concerning the research related to the manuscript

None

Figures

**Figure 1. Manhattan Plots for all tests with significant associations**
The values on the y axis represent −log10 of the uncorrected p-values from linear regression. The red line indicates the significance threshold defined as a FDR-corrected p-value of 0.05 for each test. HVLT-R, Hopkins Verbal Learning Test-Revised; DR, delayed recall; TR, total recall; JoLO, Benton Judgment of Line Orientation; TMT, Trail Making Test

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous