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. Author manuscript; available in PMC: 2015 Mar 31.
Published in final edited form as: N Engl J Med. 2013 Oct 17;369(16):1567–1568. doi: 10.1056/NEJMc1306509#SA4

TREM2 and Parkinson’s Disease

Bruno A Benitez 1; US-Spain PD research group3, Carlos Cruchaga C 1,2,*
PMCID: PMC4380008  NIHMSID: NIHMS607668  PMID: 24131187

The finding of a rare non-synonymous variant in TREM2 (p.R47H, rs75932628-T) confers risk for Alzheimer's disease (AD) (odds ratio 2 to 5),1, 2 and the finding that rare variants in other AD-related genes confer risk of several other neurodegenerative diseases,3 prompted us to ask whether R47H confers risk of Parkinson Disease.

Several other observations supported our hypothesis that TREM2 variation may confer susceptibility to Parkinson Disease. TREM2 is expressed mainly on microglia in the central nervous system and seems to mediate the phagocytosis of apoptotic neurons through TREM2 ligation4. Microgliosis has been implicated in the pathogenesis of Parkinson’s disease (PD), a neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta. Dopaminergic neurons express ligands that interact directly with TREM24 and, TREM2 mRNA levels in the SN are the second highest among all brain regions1. In addition, pathological findings of TREM2 variant carriers have shown the presence of abundant Lewy-bodies1, the hallmark of PD.

We directly genotyped rs75932628, encoding the R47H variant, in 478 PD patients and 837 healthy individuals from the Washington University in Saint Louis Movement Disorder Clinic5 as well as in 654 PD patients and 550 controls from the Memory Disorders Unit, Clínica Universidad de Navarra, School of Medicine (Pamplona, Spain)2. PD diagnosis was established according to the UK Brain Bank criteria. We found three p.R47H heterozygous carriers among the US PD cases and six among the Spanish PD cases, but in none of the screened controls (Table 1). The p.R47H variant is associated with PD in both the US (p=0.02) and in the Spanish sample (p=0.02). The combined analysis confirmed the association p.R47H variant with PD (p=4.7 × 10−3). These results suggest that the p.R47H variant not only increases risk for AD but for PD as well.

Table 1.

Association between the rs75932628-T Variant and Parkinson's Disease in two samples with different genetic background

Study MAF %
Cases		 MAF %
Controls		 p value
WU 0.3 0 0.0223
Spain 0.45 0 0.0249λ
Combined 0.0047
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*

Mantel-Haenszel Chi-Square, DF=1 for each series and 4 for the combined analysis

WU cases (n=478) and controls (n=837)

λ

Spanish cases (n=654) and controls (n=550)

Acknowledgments

Funding: This work was supported by grants from the National Institutes of Health (P30-NS069329-01), RO1NS41509, RO1NS075321, P30 NS057105, UL1 TR000448), the McDonnell Center for Cellular and Molecular Neurobiology grant, the American Parkinson Disease Association (APDA) Advanced Research Center for Parkinson Disease at Washington University in St. Louis; the Greater St. Louis Chapter of the APDA; the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), and by grant to P. Pastor from the Department of Health of the Government of Navarra (refs. 13085 and 3/2008).

Footnotes

Financial disclosure: The authors declare not conflict of interest.

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