Browsing by Subject "ALLELE"

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  • Rantalainen, Ville; Lahti, Jari; Kajantie, Eero; Tienari, Pentti; Eriksson, Johan G.; Raikkonen, Katri (2019)
    We tested if the epsilon 4 major isoform of the APOE gene and rs405509 and rs440446 promoter and intron-1 polymorphisms predicted risk of any dementia or Alzheimer's disease with diagnoses derived from the Hospital Discharge and Causes of Death Registers in 1453 participants of the Helsinki Birth Cohort Study. We used Cox proportional hazard models adjusted for sex, year of birth, maximum lifetime occupational status and education, and diagnoses of stroke, coronary heart disease, mood disorders, and depressive symptoms. APOE epsilon 4 predicted higher risk of any dementia (hazard ratios >3.68; 95% confidence interval [CI] 1.76, 7.70) across all statistical models, and when adjusted for rs405509 and rs440446. The number of minor alleles in rs405509 or rs440446 was not associated with dementia risk (hazard ratios
  • Int Genetics Consortium; Marini, Sandro; Crawford, Katherine; Tatlisumak, Turgut; Happola, Olli; Sheth, Kevin N. (2019)
    IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P <.001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
  • Malaria Genomic Epidemiology Net; Band, Gavin; Le, Quang Si; Clarke, Geraldine M.; Kivinen, Katja; Spencer, Chris C. A. (2019)
    The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as -23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations.
  • Verta, Jukka-Pekka; Jones, Felicity (2019)
    Regulation of gene expression is thought to play a major role in adaptation but there are conflicting predictions for the relative importance of cis- and trans-regulatory mechanisms in the early stages adaptive divergence. Parallel evolution of marine and freshwater threespine stickleback fish provides an excellent opportunity to dissect whether the same molecular mechanisms underlie repeated adaptive divergence in gene expression. Using RNA-seq of four marine-freshwater ecotype pairs from Scotland and Canada, we first identified genes with parallel divergence in expression and show that these are found near previously reported adaptive loci and show a molecular signature of selection centered around the transcription start site. With allele-specific expression assays in F1 hybrids we next show that expression divergence is predominantly driven by cis-regulatory control in all four river systems, a pattern that is enriched in parallel divergently expressed genes. In particular, for genes whose expression is up-regulated in parallel among freshwater fish the quantitative degree of cis- and trans-regulation is also highly correlated, suggesting a shared genetic basis across populations. This stands in contrast to genes up-regulated in parallel in marine fish, whose degree of cis- and trans-regulation is less correlated and predictable. This observed asymmetry in parallelism in how genes are up-regulated in marine and freshwater fish can be explained by differences in the evolutionary contexts of the diverging ecotypes. Finally, we show that cis-regulation is predominantly additive and shows greater robustness to different in genetic backgrounds and environmental conditions. We argue that these features make cis-regulation well-poised for rapid adaptive divergence of gene expression under conditions of on-going gene flow. Combined our study highlights how natural selection on dispersed cis-regulatory elements can shape the adaptive landscape of the genome.