All Publications

  • Signals of variation in human mutation rate at multiple levels of sequence context. Molecular biology and evolution Aikens, R. C., Johnson, K. E., Voight, B. F. 2019


    Our understanding of the human mutation rate helps us build evolutionary models and interpret patterns of genetic variation observed in human populations. Recent work indicates that the frequencies of specific polymorphism types have been elevated in Europe, and that many more, subtler signatures of global polymorphism variation may yet remain unidentified. Here, we present an analysis of the 1,000 Genomes Project supported by analysis in the Simons Genome Diversity Panel, suggesting additional putative signatures of mutation rate variation across populations and the extent to which they are shaped by local sequence context. First, we compiled a list of the most significantly variable polymorphism types in a cross-continental statistical test. Clustering polymorphisms together, we observe three sets that showed distinct shared patterns of relative enrichment among ancestral populations, and we characterize each one of these putative 'signatures' of polymorphism variation. For three of these signatures, we found that a single flanking base pair of sequence context was sufficient to determine the majority of enrichment or depletion of a polymorphism type. However, local genetic context up to 2-3 base pairs away contributes additional variability and may help to interpret a previously noted enrichment of certain polymorphism types in some East Asian groups. Moreover, considering broader local genetic context highlights patterns of polymorphism variation which were not captured by previous approaches. Building our understanding of mutation rate in this way can help us to construct more accurate evolutionary models and better understand the mechanisms that underlie genetic change.

    View details for DOI 10.1093/molbev/msz023

    View details for PubMedID 30753705

  • Systolic Blood Pressure and Risk of Type 2 Diabetes: A Mendelian Randomization Study DIABETES Aikens, R. C., Zhao, W., Saleheen, D., Reilly, M. P., Epstein, S. E., Tikkanen, E., Salomaa, V., Voight, B. F. 2017; 66 (2): 543–50


    Observational studies have shown that elevated systolic blood pressure (SBP) is associated with future onset of type 2 diabetes, but whether this association is causal is not known. We applied the Mendelian randomization framework to evaluate the causal hypothesis that elevated SBP increases risk for type 2 diabetes. We used 28 genetic variants associated with SBP and evaluated their impact on type 2 diabetes using a European-centric meta-analysis comprising 37,293 case and 125,686 control subjects. We found that elevation of SBP levels by 1 mmHg due to our genetic score was associated with a 2% increase in risk of type 2 diabetes (odds ratio 1.02, 95% CI 1.01-1.03, P = 9.05 × 10-5). To limit confounding, we constructed a second score based on 13 variants exclusively associated with SBP and found a similar increase in type 2 diabetes risk per 1 mmHg of genetic elevation in SBP (odds ratio 1.02, 95% CI 1.01-1.03, P = 1.48 × 10-3). Sensitivity analyses using multiple, alternative causal inference measures and simulation studies demonstrated consistent association, suggesting robustness of our primary observation. In line with previous reports from observational studies, we found that genetically elevated SBP was associated with increased risk for type 2 diabetes. Further work will be required to elucidate the biological mechanism and translational implications.

    View details for DOI 10.2337/db16-0868

    View details for Web of Science ID 000392691000030

    View details for PubMedID 27702834

    View details for PubMedCentralID PMC5248987