Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease

D�Souza, Tyrra; Rajkumar, Anto P.

Abstract

Objective:
Cognitive impairment and depression are among the most prevalent and most disabling non-motor symptoms in Parkinson’s disease (PD). The genetic factors that are associated with these symptoms remain uncertain. This systematic review aims to summarise the prevailing evidence from all genetic association studies investigating the genetic variants associated with cognitive impairment and depressive symptoms in people with PD.

Method:
A systematic review using five online databases: PubMed, PsycINFO, CINAHL, EMBASE and OpenGrey (PROSPERO protocol: CRD42017067431). We completed the quality assessment using the Q-Genie tool.

Results:
2353 articles were screened, and 43 articles were found to be eligible to be included. A meta-analysis of studies investigating LRRK2 rs34637584 confirmed that the minor allele carriers had significantly less cognitive impairment (p = 0.015). Further meta-analyses showed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 were associated with more depressive symptoms in PD. Moreover, APOE ϵ4 allele has been associated with more cognitive impairment in PD. BDNF (rs6265) and CRY1 (rs2287161) variants have been associated with more depressive symptoms in people with PD.

Conclusions:
PD carriers of GBA variants are at high risk for cognitive decline and depression. Screening for these variants may facilitate early identification and effective management of these non-motor symptoms. The molecular mechanisms underlying favourable cognitive functioning in LRRK2 rs34637584 variant carriers warrant further investigation.

Summations:
1.Available evidence confirms that the LRRK2 variant rs34637584 is associated with less cognitive impairment in people with PD.
2.GBA variants rs76763715 and rs421016 are associated with more severe cognitive impairment in people with PD.
3.The GBA variants rs76763715, rs421016, rs387906315 and rs80356773 have been significantly associated with the onset of depressive symptoms in PD.
Considerations:
1.This systematic review has not included studies that were not published in English. It did not include gene expression and epigenetic studies.
2.Most of the included genetic association studies were small, and they were prone to type II error.
3.There was substantial heterogeneity among the included studies.

Citation

D’Souza, T., & Rajkumar, A. P. (2019). Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease. Acta Neuropsychiatrica, 1-13. https://doi.org/10.1017/neu.2019.28

• Journal Article Type: Article
• Acceptance Date: Jun 13, 2019
• Online Publication Date: Jul 11, 2019
• Publication Date: Jul 11, 2019
• Deposit Date: Sep 4, 2019
• Publicly Available Date: Sep 4, 2019
• Journal: Acta Neuropsychiatrica
• Print ISSN: 0924-2708
• Electronic ISSN: 1601-5215
• Publisher: Cambridge University Press (CUP)
• Peer Reviewed: Peer Reviewed
• Pages: 1-13
• DOI: https://doi.org/10.1017/neu.2019.28
• Keywords: cognition; depression; Parkinson's disease; systematic review
• Public URL: https://nottingham-repository.worktribe.com/output/2562764
• Publisher URL: https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/systematic-review-of-genetic-variants-associated-with-cognitive-impairment-and-depressive-symptoms-in-parkinsons-disease/7CDCBD70DA89F069F304904232DC1EBD
• Additional Information: License: © Scandinavian College of Neuropsychopharmacology 2019