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The article focuses on several advances in functional genomics and translational biology in 2015 which include micro-RNAs, short regulatory elements that have emerged as key players in cardiometabolic disease pathogenesis and the publication of a resource of 111 reference human epigenomes.

The article discusses the scientific advances in functional genomics and translational biology in 2014. These include the discovery of large intergenic noncoding RNAs (lincRNAs), the use of founder populations to conduct genome-wide association studies and the development of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitory antibodies for coronary artery disease prevention and serum low-density lipoprotein reduction.

The article presents a study regarding the prevalence of atrial fibrillation (AF) among carriers and noncarriers of rare variants previously designated as pathogenic for AF. The study concluded that these variants are not associated with AF and suggested that caution is needed when ascribing variants as pathogenic or causative. The methods of the study are discussed.

Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis.A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency 0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result.Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis. [ABSTRACT FROM AUTHOR]

Background: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk., Methods: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort., Results: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes., Conclusions: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility., Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score., Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 -8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 -6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 -3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005)., Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF., Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation., Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P <0.001) and had fewer clinical risk factors for AF ( P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P <0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P <0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P =0.13)., Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Background: The majority of out-of-hospital cardiac arrests (OHCAs) occur in residential locations, but knowledge about strategic placement of automated external defibrillators in residential areas is lacking. We examined whether residential OHCA areas suitable for placement of automated external defibrillators could be identified on the basis of demographic characteristics and characterized individuals with OHCA in residential locations., Methods and Results: We studied 4828 OHCAs in Copenhagen between 1994 and 2005. The incidence and characteristics of OHCA were examined in every 100 x 100-m (109.4 x 109.4-yd) residential area according to its underlying demographic characteristics. By combining > or =2 demographic characteristics, it was possible to identify 100 x 100-m (109.4 x 109.4-yd) areas with at least 1 arrest every 5.6 years (characterized by >300 persons per area and lowest income) to 1 arrest every 4.3 years (characterized by >300 persons per area, lowest income, low education, and highest age). These areas covered 9.0% and 0.8% of all residential OHCAs, respectively. Individuals with OHCA in residential locations differed from public ones in that the patients were older (70.6 versus 60.6 years; P<0.0001), the ambulance response interval was longer (6.0 versus 5.0 minutes; P<0.0001), arrests occurred more often at night (21.2% versus 11.2%; P<0.0001), the patients had ventricular fibrillation less often (12.8% versus 38.1%; P<0.0001), and the patients had a worse 30-day survival rate (3.2% versus 13.9%; P<0.0001)., Conclusions: On the basis of simple demographic characteristics of a city center, we could identify residential areas suitable for automated external defibrillator placement. Individuals with OHCA in residential locations were more likely to have characteristics associated with poor outcome compared with public arrests.