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

NEUROBIOLOGY OF AGING

卷:56

Article

Mata, Ignacio F.^1,2  Johnson, Catherine O.³  Leverenz, James B.⁴  Weintraub, Daniel^5,6,7  Trojanowski, John Q.^8,9  Van Deerlin, Vivianna M.⁸  Ritz, Beate^10,11  Rausch, Rebecca¹¹  Factor, Stewart A.¹²  Wood-Siverio, Cathy¹²  Quinn, Joseph F.^13,14  Chung, Kathryn A.^13,14  Peterson-Hiller, Amie L.^13,14  Espay, Alberto J.¹⁵  Revilla, Fredy J.^16,17  Devoto, Johnna¹⁵  Yearout, Dora^1,2  Hu, Shu-Ching^1,2  Cholerton, Brenna A.^1,18  Montine, Thomas J.¹⁹  Edwards, Karen L.³  Zabetian, Cyrus P.^1,2 

[1] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA

[2] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA

[3] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA

[4] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Neurol Inst, Cleveland, OH 44106 USA

[5] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[7] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA

[8] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[9] Univ Penn, Inst Aging, Philadelphia, PA 19104 USA

[10] Univ Calif Los Angeles, Sch Publ Hlth, Dept Environm Hlth Sci, Los Angeles, CA 90024 USA

[11] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA

[12] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[13] Portland VA Med Ctr, Portland, OR USA

[14] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA

[15] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH USA

[16] Div Neurol Greenville Hlth Syst, Greenville, SC USA

[17] Univ South Carolina, Sch Med, Greenville, SC USA

[18] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[19] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA

关键词: Parkinson's disease;    NeuroX;    Cognitive impairment;    Genetics;   

DOI  :  10.1016/j.neurobiolaging.2017.04.009

来源: Elsevier

【 摘 要 】

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 (LetterNumber 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-alue (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; PFDR = 2.7 x 10(-4)) for JoLO, PARP4 rs9318600 (P-FDR = 0.006), and rs9581094 (PFDR = 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. Published by Elsevier Inc.

【 授权许可】

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