Objective This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European‐ancestry subjects, and to increase the diversity in PD genome‐wide association (GWAS) data. Methods We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p‐value <1 × 10−5 were tested in a replication cohort of 1,234 self‐reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. Results One locus, SNCA, achieved genome‐wide significance (p‐value <5 × 10−8); rs356182 achieved genome‐wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35–1.86, p‐value 2.48 × 10−8; 23andMe, G allele: 1.26 OR, 95% CI 1.16–1.37, p‐value 4.55 × 10−8). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single‐ancestry test (p‐value <5 × 10−5). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single‐ancestry test (p‐value <5 × 10−5). Interpretation This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353–365

BackgroundWiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.MethodsWe performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants.ResultsBiallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function.ConclusionBiallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.

The Drosophila cold acclimation gene (Dca) is involved in the adaptive response to low temperatures. This gene is upregulated at the transcriptional level when D. melanogaster flies are exposed 1 day to 15 °C. Dca (or smp-30) is a member of the SMP-30/Gluconolactonase/LRE-like family. In the current study, we characterized the members of this gene family in the 12 Drosophila species with available complete genomes sequences. Two paralogous genes, Dca and regucalcin, were identified in all the Sophophora subgenus species (9 of the 12 species), and their presence was further confirmed in three other species of the subgenus (D. subobscura, D. madeirensis, and D. guanche). However, only regucalcin was present in the species of the Drosophila subgenus (D. grimshawi, D. virilis, and D. mojavensis). The phylogenetic analysis and the molecular organization of Dca that is a nested intronic gene support that Dca arose by a duplication event from the ancestral regucalcin gene after the split of the Sophophora and Drosophila subgenera but before the Sophophora radiation. After the duplication event, the nonsynonymous fixation rate increased in the branch leading to Dca (but not to regucalcin), suggesting the neofunctionalization of the former duplicate. Thus, regucalcin would have maintained the ancestral gene function, and Dca would have acquired a new function likely related to Ca²⁺ homeostasis and cold acclimation. Molecular evolution of Dca has been affected by its implication in the adaptive response to cold temperatures. Indeed, the gene has evolved under stronger purifying selection in the temperate than in the tropical Sophophora species, as reflected by the ratio of nonsynonymous to synonymous substitutions. This result is consistent with functional constraints acting on the DCA protein to keep species adaptation to temperate climates. Dca and regucalcin also differ in their expression patterns. The expression profile of regucalcin is similar to that of the anterior fat body protein gene (AFP) of Sarcophaga peregrina and Calliphora vicina, which is also a member of the SMP-30/Gluconolactonase/LRE-like gene family. Sequence similarity and expression profile suggest that AFP and regucalcin are indeed orthologous genes.

Recently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein.In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.

Introduction: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-ɛ4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics. Objective: The objective of this study was to evaluate the BIN1 3′ intergenic region DNA methylation patterns in a Colombian sample of LOAD patients. Methods: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD. Results: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05). Conclusions: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.

Background Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non‐European populations. In addition, the overall identification of copy number variants at a genome‐wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome‐wide burden of copy number variants in Latinos and its association with Parkinson's disease. Methods We used genome‐wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. Results Genome‐wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69–10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10−7). Conclusions We found that although overall genome‐wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early‐onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome‐wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society

Objective: We evaluated the association of several single-nucleotide polymorphisms in the triggering receptor expressed on myeloid cells 2 (TREM2) gene in a Colombian sample of late-onset Alzheimer disease (LOAD). Methods: The p.Q33* (rs104894002), p.R47H (rs75932628), p.R62H (rs143332484), and p.D87N (rs142232675) variants of TREM2 gene were directly genotyped using KASPar technology in 358 cases and 329 healthy controls. Sanger sequencing was used to validate >10% of KASPar’s results. The Fisher exact test was used to compare the distribution of allelic and genotype frequency between cases and controls, and the Bonferroni correction was set at P<0.05. Results: The minor allele frequency of rs75932628-T was 0.009 in cases and was not found in any healthy controls which suggests a significant association between rs75932628-T and LOAD risk in our sample (P=0.010). The rs143332484-T variant did not exhibit a significant association (P=0.160), whereas rs104894002 and rs142232675 were not found. Conclusions: Our findings suggest that the rs75932628-T variant of TREM2 is an important risk factor for LOAD in the Colombian population.

To date, over 90 Parkinson’s disease (PD) risk variants have been reported from genome-wide association studies (GWAS). However, these GWAS efforts have been limited to individuals of European and East Asian ancestry. We performed the first GWAS of Latino PD patients from South America, comparing 807 cases against 690 controls followed by association testing of suggestive loci in a replication cohort of 1,234 cases and 439,522 controls. We demonstrated that SNCA plays a significant role in PD etiology in a Latino cohort and identified a suggestive locus near NRROS on chromosome 3 that appeared to be driven by Peruvian subjects. We also characterized the overlap of PD genetic architecture between Europeans and Latinos with a replication of significant variants identified by Nalls et al. in their 2019 GWAS1, finding 80% concordance in direction of effect. We then leveraged the population history of Latinos via admixture mapping, identifying a significant locus on chromosome 14 in a joint test of ancestries, driven by the Native American ancestral background, and a significant locus on chromosome 6 in our test of African ancestry, containing the genes STXBP6 and RPS6KA2, respectively. Ultimately, our work reflects the most comprehensive characterization of PD genetic architecture in Latinos to date.