A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

MicroHapDB: A Portable and Extensible Database of All Published Microhaplotype Marker and Frequency Data.

Microhaplotypes are the subject of significant interest in the forensics community as a promising multi-purpose forensic DNA marker for human identification. Microhaplotype markers are composed of multiple SNPs in close proximity, such that a single NGS read can simultaneously genotype the individual SNPs and phase them in aggregate to determine the associated donor haplotype. Abundant throughout the human genome, numerous recent studies have sought to discover and rank microhaplotype markers according to allelic diversity within and among populations. Microhaplotypes provide an appealing alternative to STR markers for human identification and mixture deconvolution, but can also be optimized for ancestry inference or combined with phenotype SNPs for prediction of externally visible characteristics in a multiplex NGS assay. Designing and evaluating panels of microhaplotypes is complicated by the lack of a convenient database of all published data, as well as the lack of population allele frequency data spanning disparate marker collections. We present MicroHapDB, a comprehensive database of published microhaplotype marker and frequency data, as a tool to advance the development of microhaplotype-based human forensics capabilities. We also present population allele frequencies derived from 26 global population samples for all microhaplotype markers published to date, facilitating the design and interpretation of custom multi-source panels. We submit MicroHapDB as a resource for community members engaged in marker discovery, population studies, assay development, and panel and kit design.

Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death.

Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex- and coronary artery disease-stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval-associated single-nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non-ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.