Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

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

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.

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