scholarly journals Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort

2021 ◽  
Author(s):  
Matteo Bianchi ◽  
Sergey V. Kozyrev ◽  
Antonella Notarnicola ◽  
Lina Hultin Rosenberg ◽  
Åsa Karlsson ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Disease Susceptibility ◽  
Rare Genetic Variation

scholarly journals Genetic and Environmental Predictors of Adolescent PTSD Symptom Trajectories Following a Natural Disaster

2019 ◽  
Vol 9 (6) ◽  
pp. 146 ◽  
Author(s):  
Sheerin ◽  
Kovalchick ◽  
Overstreet ◽  
Rappaport ◽  
Williamson ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Environmental Factors ◽  
Natural Disaster ◽  
Symptom Improvement ◽  
Ptsd Symptoms ◽  
Environmental Predictors ◽  
Longitudinal Course ◽  
Symptom Trajectories ◽  
Rare Genetic Variation ◽  
Over Time

: Genes, environmental factors, and their interplay affect posttrauma symptoms. Although environmental predictors of the longitudinal course of posttraumatic stress disorder (PTSD) symptoms are documented, there remains a need to incorporate genetic risk into these models, especially in youth who are underrepresented in genetic studies. In an epidemiologic sample tornado-exposed adolescents (n = 707, 51% female, Mage = 14.54 years), trajectories of PTSD symptoms were examined at baseline and at 4-months and 12-months following baseline. This study aimed to determine if rare genetic variation in genes previously found in the sample to be related to PTSD diagnosis at baseline (MPHOSPH9, LGALS13, SLC2A2), environmental factors (disaster severity, social support), or their interplay were associated with symptom trajectories. A series of mixed effects models were conducted. Symptoms decreased over the three time points. Elevated tornado severity was associated with elevated baseline symptoms. Elevated recreational support was associated with lower baseline symptoms and attenuated improvement over time. Greater LGLAS13 variants attenuated symptom improvement over time. An interaction between MPHOSPH9 variants and tornado severity was associated with elevated baseline symptoms, but not change over time. Findings suggest the importance of rare genetic variation and environmental factors on the longitudinal course of PTSD symptoms following natural disaster trauma exposure.

scholarly journals Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

2019 ◽  
Vol 7 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Detelina Grozeva ◽  
Salha Saad ◽  
Georgina E. Menzies ◽  
Rebecca Sims
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Rare Genetic Variation

scholarly journals Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity

Endocrine ◽  
2015 ◽  
Vol 52 (2) ◽  
pp. 277-286 ◽  
Author(s):  
Jasmijn K. Van Camp ◽  
Fenna De Freitas ◽  
Doreen Zegers ◽  
Sigri Beckers ◽  
Stijn L. Verhulst ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genomic Region ◽  
Human Obesity ◽  
Rare Genetic Variation

scholarly journals Rare Genetic Variation Underlying Human Diseases and Traits: Results from 200,000 Individuals in the UK Biobank

2020 ◽  
Author(s):  
Sean J. Jurgens ◽  
Seung Hoan Choi ◽  
Valerie N. Morrill ◽  
Mark Chaffin ◽  
James P. Pirruccello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Variation ◽  
Exome Sequencing ◽  
Human Diseases ◽  
Disease Genes ◽  
Uk Biobank ◽  
Novel Genes ◽  
Pathogenic Variants ◽  
Rare Genetic Variation ◽  
The Uk

AbstractBackgroundMany human diseases are known to have a genetic contribution. While genome-wide studies have identified many disease-associated loci, it remains challenging to elucidate causal genes. In contrast, exome sequencing provides an opportunity to identify new disease genes and large-effect variants of clinical relevance. We therefore sought to determine the contribution of rare genetic variation in a curated set of human diseases and traits using a unique resource of 200,000 individuals with exome sequencing data from the UK Biobank.Methods and ResultsWe included 199,832 participants with a mean age of 68 at follow-up. Exome-wide gene-based tests were performed for 64 diseases and 23 quantitative traits using a mixed-effects model, testing rare loss-of-function and damaging missense variants. We identified 51 known and 23 novel associations with 26 diseases and traits at a false-discovery-rate of 1%. There was a striking risk associated with many Mendelian disease genes including: MYPBC3 with over a 100-fold increased odds of hypertrophic cardiomyopathy, PKD1 with a greater than 25-fold increased odds of chronic kidney disease, and BRCA2, BRCA1, ATM and PALB2 with 3 to 10-fold increased odds of breast cancer. Notable novel findings included an association between GIGYF1 and type 2 diabetes (OR 5.6, P=5.35×10−8), elevated blood glucose, and lower insulin-like-growth-factor-1 levels. Rare variants in CCAR2 were also associated with diabetes risk (OR 13, P=8.5×10−8), while COL9A3 was associated with cataract (OR 3.4, P=6.7×10−8). Notable associations for blood lipids and hypercholesterolemia included NR1H3, RRBP1, GIGYF1, SCGN, APH1A, PDE3B and ANGPTL8. A number of novel genes were associated with height, including DTL, PIEZO1, SCUBE3, PAPPA and ADAMTS6, while BSN was associated with body-mass-index. We further assessed putatively pathogenic variants in known Mendelian cardiovascular disease genes and found that between 1.3 and 2.3% of the population carried likely pathogenic variants in known cardiomyopathy, arrhythmia or hypercholesterolemia genes.ConclusionsLarge-scale population sequencing identifies known and novel genes harboring high-impact variation for human traits and diseases. A number of novel findings, including GIGYF1,represent interesting potential therapeutic targets. Exome sequencing at scale can identify a meaningful proportion of the population that carries a pathogenic variant underlying cardiovascular disease.

scholarly journals De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

2019 ◽  
Author(s):  
Michael D. Kessler ◽  
Douglas P. Loesch ◽  
James A. Perry ◽  
Nancy L. Heard-Costa ◽  
Brian E. Cade ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Mutation Rate ◽  
De Novo ◽  
Population Level ◽  
Mutation Rates ◽  
Founder Population ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Nucleotide Mutation ◽  
Rare Genetic Variation

Abstractde 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 directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, 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, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

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