Analysis of common and rare VPS13C variants in late-onset Parkinson disease

Objective We aimed to study the role of coding VPS13C variants in a large cohort of patients with lateonset Parkinson disease (PD) (LOPD). Methods VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis. Results No biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit. Conclusions Our results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD

GBA variants in REM sleep behavior disorder: a multicenter study

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

HLA in isolated REM sleep behavior disorder and Lewy body dementia

peer reviewedSynucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95 CI = 1.27–1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95\%CI = 1.12–1.41, p = 8.76e-05), 70Q (OR = 0.81, 95\%CI = 0.72–0.91, p = 3.65e-04) and 71R (OR = 1.21, 95\%CI = 1.08–1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies

Data from: Morphological and genetic analysis of sympatric dace within the Rhinichthys cataractae species complex: a case of isolation lost

The Nooksack dace (Pisces: an undescribed putative taxon within Rhinichthys) and longnose dace (Rhinichthys cataractae) are two forms within the R. cataractae species complex that are distinguishable from one another by mitochondrial (mt) DNA divergence of 2–3%, as well as by subtle morphological differences. The two forms are found in allopatry in south-eastern British Columbia (BC), Canada, and adjacent areas of western Washington, USA, and are sympatric in three streams in the lower Fraser River valley, BC, and may represent cryptic species. We assayed 12 morphometric traits and two meristic characters (N = 582; 23 sampling locations) to test for diagnosability of the two dace, as well as to test for morphological differentiation by mtDNA type in sympatry. We then employed a 10-locus microsatellite DNA assay (N = 374; 12 sampling locations) to test for genetic distinction between Nooksack dace and longnose dace in sympatry. We found that the two dace could not be reliably differentiated morphologically: there was overlap in all characters measured, and sampling location had a much larger effect on morphology than mtDNA group. Microsatellite analysis showed no distinction by mtDNA type in localities with sympatric dace, indicating complete admixture between the sympatric Nooksack dace and longnose dace. The Nooksack dace and longnose dace provide an example of ‘ephemeral speciation’: two lineages that, despite an estimated 1.1 Myr of isolation, have developed no apparent barriers to reproduction and appear to have collapsed into a single interbreeding population where they come into secondary contact. Nonetheless, the zone of secondary contact and the diagnosability of the Nooksack dace in terms of mtDNA represent significant aspects of the evolutionary legacy within R. cataractae and support its conservation importance

Phylogeography of the longnose dace (Rhinichthys cataractae) species group in northwestern North America – the Nooksack dace problem

The longnose dace (Cyprinidae: Rhinichthys cataractae (Valenciennes 1842)) is one of the most widespread freshwater fishes in North America and across this range there have been several divergent forms described that are of uncertain taxonomic status. One of these forms, the Nooksack dace, is found in southwestern British Columbia and adjacent portions of western Washington State, and is distinguished from longnose dace by a lower number of lateral line scales. We sequenced a total of approximately 1,400 base pairs of mitochondrial DNA and found that the longnose dace found west of the continental divide and Nooksack dace constituted reciprocally-monophyletic clades that differed from each other by between 2 and 3% sequence divergence. Sequence analysis at two nuclear loci (the S7 ribosomal protein and recombination activation gene 1 introns, ~1,600 base pairs), however, showed no consistent difference between longnose dace and Nooksack dace and several alleles were shared between them. By contrast, consistent differences both at mitochondrial and nuclear DNA loci were resolved between R. cataractae samples from east and west of the Continental Divide. The Nooksack dace does not appear to warrant separate taxonomic status from the longnose dace, but the mitochondrial DNA differences support its recognition as an important component of the evolutionary and biogeographic legacy of R. cataractae.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

jruskey_usat-data_genepop-format

Microsatellite DNA genotypes in base pair

jruskey&taylor_morphological-data

Morphological data for Ruskey and Taylor. All are in mm except two count