Genetic risk factors in Finnish patients with Parkinson's disease

Abstract

Introduction Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. Methods The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). Results We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. Conclusions The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…We also compared the ortholog list to genes that have been identified as candidate risk genes for any human α-synucleinopathy by examining genome-wide association or whole exome sequencing studies from MSA (X. Gu et al, 2018;Sailer et al, 2016), PD (Chang et al, 2017;Guo et al, 2018;Jansen et al, 2017;Li et al, 2018;Quadri et al, 2015;Robak et al, 2017;Sandor et al, 2017;Schormair et al, 2018;Shulskaya et al, 2018;Siitonen et al, 2017;Ylönen et al, 2017), or DLB (Guerreiro et al, 2018;Keogh et al, 2016;Peuralinna et al, 2015). In total, we found 30 transcripts with a mammalian ortholog that had also been identified in one or more of these studies (Table 7).…”

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

“…Variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are among the most common risk factors for PD, found in 3%‐20% of PD patients from different populations . Recently, mutations in another lysosomal gene involved in sphingolipid metabolism, SMPD1 , which encodes the lysosomal enzyme acid sphingomyelinase (ASMase), have also been associated with an increased risk for PD . In the Ashkenazi Jewish population, specific Niemann‐Pick type A (NPA)‐causing SMPD1 mutations, p.L302P (also called p.L304P) and p.fsP330 (also called p.F333Sfs*52 or c.996delC), were associated with PD in 2 independent studies .…”

“…In the Ashkenazi Jewish population, specific Niemann‐Pick type A (NPA)‐causing SMPD1 mutations, p.L302P (also called p.L304P) and p.fsP330 (also called p.F333Sfs*52 or c.996delC), were associated with PD in 2 independent studies . In addition, 2 studies in Chinese populations and 2 studies in European populations identified additional SMPD1 mutations and variants associated with PD …”

“…[3][4][5][6][7][8][9] Recently, mutations in another lysosomal gene involved in sphingolipid metabolism, SMPD1, which encodes the lysosomal enzyme acid sphingomyelinase (ASMase), have also been associated with an increased risk for PD. [10][11][12][13][14][15][16][17] In the Ashkenazi Jewish population, specific Niemann-Pick type A (NPA)-causing SMPD1 mutations, p.L302P (also called p.L304P) and p.fsP330 (also called p.F333Sfs*52 or c.996delC), were associated with PD in 2 independent studies. 11,15 In addition, 2 studies in Chinese populations and 2 studies in European populations identified additional SMPD1 mutations and variants associated with PD.…”

“…11,15 In addition, 2 studies in Chinese populations and 2 studies in European populations identified additional SMPD1 mutations and variants associated with PD. 12,13,16,17 Both GCase and ASMase hydrolyze sphingolipids in the lysosome and generate a common product, ceramide, suggesting that they may lead to PD in a similar manner. 1 ASMase is responsible for the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, and biallelic mutations in SMPD1 lead to NPA or Niemann-Pick type B (NPB), 18 the acute neurovisceral and chronic visceral forms, respectively, of ASMase deficiency.…”