This study identifies the candidate gene regions LOC100505836, SLC25A48, UNC13B, SLCO3A1, WNT3, and NSF as new candidates for PD using an AJ case-control population as a discovery dataset and two other large publicly available dataset as replication datasets. By utilizing a relatively genetically homogeneous AJ population and searching for variants that are rare (defined as a MAF threshold of 2% or higher), we report additional susceptibility variants for PD. In addition, we examined the magnitude of association of previously reported PD candidate genes including MAPT, SNCA, LRRK2, GBA, PARK16, BST1, HLA, SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R in the AJ dataset and found them to be comparable to several reports in North American and European populations.
Of the new candidate genes that we identified in this study, many represent interesting candidates for PD based on function, as discussed below, and warrant additional follow up in independent studies and different PD populations. Functional studies suggest a role for three of the genes that we identified (SLC25A48, UNC13B
, and NSF
) in neuronal signalling and the dopamine pathway. SLC25A48
is a member of the solute carrier family 25 proteins that function as transporters of a large variety of molecules including ATP/ADP and amino acids [32
]. Characterized SLC25s localize to the inner mitochondrial membrane and are also often referred to as mitochondrial carriers or uncoupling proteins (UCPs) [33
is highly expressed in the central nervous system (CNS) including the hypothalamus, pituitary and brainstem and has been shown to be important in healthy neurons for energy production and to have a role in neuronal signalling [34
]. Previous studies have suggested a role for mitochondrial UCPs in PD, Alzheimer disease and amyotrophic lateral sclerosis [32
The SNP rs10121009, located in UNC13B
) was included in the top 57 SNPs in the AJ dataset and also showed evidence of strong association in a meta-analysis for all three datasets (p = 2.75 × 10-6
). Experiments in C. elegans and mammalian cellular models systems suggest a role for the MUNC13 family of proteins in the priming of synaptic and secretory vesicles in a step just preceding fusion with the plasma membrane. MUNC13
has been shown to control the release of both neurotransmitters and neuropeptides from motorneurons in the Caenorhabditis elegans (C.elegans) neuromuscular junction [35
]. The lipids and proteins involved in these networks are highly conserved between C. elegans and mammals.
are closely located to MAPT
and multiple datasets show support for possible association with PD, we examined this region encompassing MAPT-NSF-WNT3
further. Our data support the possibility that a variant(s) in the NSF
may contribute to PD, independent of MAPT
. This association was replicated in the NINDS dataset, but not in the CIDR/pankratz et al 2009 dataset because the CIDR/Pankratz et al 2009 dataset lacked the associated SNP in WNT3
. Taken together and based on the function of these genes, there is suggestive evidence that NSF
are candidate genes that need to be further studied. The function of NSF
in vesicular trafficking and membrane fusion is well documented and the protein has also been shown to play a role in the fusion of synaptic vesicles in the presynaptic membrane during neurotransmission and to interact with neurotransmission receptors at the postsynaptic side [36
]. More recent studies suggest an interaction between NSF
and the Dopamine D1 receptor (D1R) which is important for the membrane localization of D1R [37
]. D1R plays important roles in regulating motor coordination, working memory, learning and reward and D1R dysfunction is as associated with both psychiatric and neurological disorders including PD [38
is a member of the WNT
gene family which encode secreted signaling proteins that play a role in several developmental processes, including embryonic and adult neurogenesis. Postnatal neurogenesis has been observed in two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, among vertebrates including human. Genetic factors essential for neural development including WNT3 are also expressed in adult neurogenic regions. Cell proliferation of neural progenitors in the SVZ of PD patients and animal models has been shown to be decreased and modulated by dopamine.
We also replicate association of several previously identified PD genes and loci in our AJ population including MAPT, SNCA, LRRK2, GBA, PARK16, BST1, STK39 and LAMP3. Both LRRK2 and GBA represent the most common risk factors in the AJ PD population. In the AJ dataset, we observed a significant association for the LRRK2 'G2019S' mutation as well as for a single haplotype, and these findings are consistent with previously published studies. Among 268 PD cases, 31 (11.6%) individuals carried the LRRK2 G2019S mutation, and their mean age at onset was younger/similar to non-carriers (mean age at onset of 56.5 (SD = 11.1) vs. 60.3 (SD = 12.3), respectively). The GBA 'N370S' mutation is the most common allele reported in AJ PD cases in several studies however a risk haplotype supporting a founder effect has not been previously reported. In our AJ PD dataset we identified a risk haplotype of 'ATG' (GBA 'N370S', rs2049805 and rs1045253)(p = 8.19 × 10-4) spanning ~12.5 Kb suggesting that these individuals share a common founder. Among 268 PD cases, 28 individuals carried the GBA N370S mutation (10.4%), and their mean age at onset was younger/similar to non-carriers (mean age at onset of 57.4 (SD = 12.4) vs. 60.2 (SD = 12.1), respectively).
Our analysis of the PARK16
locus in our AJ dataset confirms the finding of Satake et al (2009) [13
] in a Japanese population and suggests that NUCKS1
is a promising candidate for PARK16
. More recently, Tucci et al (2010) [39
] analysed the coding regions of 3 candidate genes (NUCKS1, RAB7L1
, and SLC41A1
) at PARK16
in a British cohort of 182 PD patients. Novel mutations were identified in 1 PD patient in RAB7L1
(K157R) and in another patient in SLC41A1
(A350 V). Follow-up studies including re-sequencing of the NUCKS1
gene and other candidate genes at the PARK16
region are warranted.
In summary, our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway. Although the power to detect genome-wide level significance in the AJ dataset was low because of the small sample size we have demonstrated the utility of this dataset in gene and SNP discovery both by replication in dbGaP datasets with a larger sample size combined with joint analyses and by replicating association of previously identified PD susceptibility genes. Follow-up genotyping, replication studies and sequencing will be needed to confirm our findings in future studies.