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It has been postulated that rare coding variants (RVs; MAF5%, with height having the highest h2RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h2RV, enabling the assessment of gene-level characteristics and revealing 12 novel gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, novel methods are needed to predict RV functionality.

Background: Atherosclerotic cardiovascular diseases (CVDs) are leading causes of death despite effective therapies and result in unnecessary morbidity and mortality throughout the world. We aimed to investigate the cost-effectiveness of polygenic risk scores (PRS) to guide statin therapy for Canadians with intermediate CVD risk and model its economic outlook. Methods: This cost-utility analysis was conducted using UK Biobank prospective cohort study participants, with recruitment from 2006 to 2010, and at least 10 years of follow-up. We included nonrelated white British-descent participants (n=96 116) at intermediate CVD risk with no prior lipid lowering medication or statin-indicated conditions. A coronary artery disease PRS was used to inform decision to use statins. The effects of statin therapy with and without PRS, as well as CVD events were modelled to determine the incremental cost-effectiveness ratio from a Canadian public health care perspective. We discounted future costs and quality-adjusted life-years by 1.5% annually. Results: The optimal economic strategy was when intermediate risk individuals with a PRS in the top 70% are eligible for statins while the lowest 1% are excluded. Base-case analysis at a genotyping cost of $70 produced an incremental cost-effectiveness ratio of $172 906 (143 685 USD) per quality-adjusted life-year. In the probabilistic sensitivity analysis, the intervention has approximately a 50% probability of being cost-effective at $179 100 (148 749 USD) per quality-adjusted life-year. At a $0 genotyping cost, representing individuals with existing genotyping information, PRS-guided strategies dominated standard care when 12% of the lowest PRS individuals were withheld from statins. With improved PRS predictive performance and lower genotyping costs, the incremental cost-effectiveness ratio demonstrates possible cost-effectiveness under thresholds of $150 000 and possibly $50 000 per quality-adjusted life-year. Conclusions: This study suggests that using PRS alongside existing guidelines might be cost-effective for CVD. Stronger predictiveness combined with decreased cost of PRS could further improve cost-effectiveness, providing an economic basis for its inclusion into clinical care.

Objective Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH). Methods We employed a CH discovery (N=4,312) and independent validation sample (N=1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (N=1,239). We also tested the CH-PRS in an independent replication CH cohort (N=200) and brain autopsy cohort (N=33). Finally, we tested the effect of ancestry on PRS by employing European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS"). Results The full model (LOAD ~ CH-PRS + sex + age + APOE-i4), achieved an AUC=74% (ORCH-PRS =1.51 95%CI=1.36-1.68), raising to >75% in APOE-i4 non-carriers. CH-PRS alone achieved an AUC=72% in the autopsy cohort, raising to AUC=83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR=1.61, 95%CI=1.19-2.17) and significantly predicted conversion to LOAD (HR=1.93, CI=1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC=58% and 53%, respectively). Interpretation Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. This article is protected by copyright. All rights reserved.

Background and Purpose— Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods— Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results— ABCC6 , KRIT1 , CECR1 , COL3A1 , COL4A1 , COL4A2 , COLGALT1 , GLA , HTRA1 , NOTCH3 , RNF213 , and TREX1 harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%–37.5%) while lower total frequencies were estimated for in silico–predicted likely damaging variants (14.9%–19.7%) and pathogenic clinical variants (0.7%–2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions— Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.

Background and ObjectivesLow buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies.MethodsFirst, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE). Then, we performed 2-sample mendelian randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS) score. Genetic variants associated with mtDNA-CN levels were derived from the UK Biobank study (N = 383,476), and corresponding effects on 3-month mRS score were ascertained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME; N = 6,021) study.ResultsA 1-SD lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS score: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.19–1.36; p = 4.7 × 10−12). Independently of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS score: OR 1.16, 95% CI 1.08–1.24; p = 4.4 × 10−5), poor functional outcome status (mRS score 3–6 vs 0–2: OR 1.21, 95% CI 1.08–1.34; p = 6.9 × 10−4), and mortality (OR 1.35, 95% CI 1.14–1.59; p = 3.9 × 10−4). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (net reclassification index [NRI] score 0.16, 95% CI 0.08–0.23; p = 3.6 × 10−5) and mortality (NRI score 0.31, 95% CI 0.19–0.43; p = 1.7 × 10−7) beyond known prognosticators. With the use of independent datasets, mendelian randomization revealed that a 1-SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS score (OR 2.35, 95% CI 1.13–4.90; p = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05–6.86; p = 0.04).DiscussionBuffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes.Classification of EvidenceThis study provides Class II evidence that low buffy coat mtDNA-CN (>1 SD) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.

Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. Methods: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. Results: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor–like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70–0.88; P =1.46×10 −5 ) and TNFSF12 (OR=0.86; 95% CI, 0.81–0.91; P =7.69×10 −7 ) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31–1.78; P =3.32×10 −8 ) and intracerebral (OR=1.34; 95% CI, 1.14–1.58; P =4.05×10 −4 ) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47–0.81; P =5.20×10 −4 ). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. Conclusions: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called “AutoMitoC”. We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Overall, genetic analyses identified 73 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18-0.29; P=2.6×10−19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7×10−8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5×10−4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS). We propose a method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A calibrated RVGRS strongly associates with coronary artery disease (CAD) in European and South Asian populations by capturing the aggregate effect of rare variants through a polygenic model of inheritance. The RVGRS identifies 1.5% of the population with substantial risk of early CAD and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and a common variant genetic risk score., Identifying associations of rare variants with disease is challenging due to small effect sizes, technical artefacts and population structure heterogeneity. Here, the authors present RV-EXCALIBER, a method that uses large summary-level exome data to robustly calibrate rare variant burden.

PURPOSE OF REVIEW This review is a comprehensive update on recent discoveries on the genetics of early-onset coronary artery disease (EOCAD), and how those findings can be translated to advance its medical management. RECENT FINDINGS To date, a total of 266 common variants of modest effect size have been reported to be associated with CAD, but many still warrant functional studies. Rare variants impacting the function of at least 10 genes are now well characterized in Mendelian EOCAD. Estimations of minor allele frequencies in multiple ancestries from large genetic databases have allowed us to estimate the prevalence of Mendelian forms of EOCAD. In fact, the prevalence of Mendelian mutations varies markedly between ancestries, ranging from 1 : 289 to 1 : 153 for familial hypercholesterolemia. Mendelian forms of EOCAD support three major biological pathways, including lipid metabolism, vascular wall integrity and function, and thrombosis. Furthermore, combining common variants of modest effect into polygenic risk scores (PRS) has shown to be effective at identifying individuals at high risk of CAD. SUMMARY Mendelian forms of EOCAD highlight the importance of lipid metabolism, yet prevalence in many non-European populations remains to be clarified. Polygenic EOCAD affects more individuals and, in many cases, confers a higher risk of EOCAD than rare Mendelian mutations. Thus, sequencing of target genes and the derivation of PRSs can be used to identify high-risk patients, leading to more personalized therapeutic approaches.

We report a novel homozygous apolipoprotein A5 (APOA5) frameshift mutation (c.G425del-C, p.Arg143AlafsTer57) identified in a 12-year-old boy of Pakistani origin with severe hypertriglyceridemia (up to 35 mmol/L) and type V hyperlipoproteinemia. The patient did not respond to fibrate therapy, but his condition improved under a very low fat diet, although compliance was suboptimal. Heterozygous status was detected in both parents (consanguineous union) and one sibling, all showing moderate hypertriglyceridemia (between 5 and 10 mmol/L). There was a significant family history of premature cardiovascular disease. The index case was also diagnosed with a coronary artery anomaly. Considering the recently reported association of rare mutations in APOA5 with the risk of early myocardial infarction, we discuss the implications of these findings for the young man and his family.

Background Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with early-onset coronary artery disease (EOCAD). We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants, with a combined effect similar to Mendelian forms of coronary artery disease, such as familial hypercholesterolemia. Methods and Results To confirm the polygenic contribution to EOCAD (age of ≤40 years for men and ≤45 years for women), we calculated in 111 418 British participants from the UK Biobank cohort a genetic risk score (GRS) based on the presence of 182 independent variants associated with coronary artery disease (GRS182). Participants with a diagnosis of EOCAD who underwent a revascularization procedure (n=96) had a significantly higher GRS182 ( P =3.21×10 −9 ) than those without EOCAD. An increase of 1 SD in GRS182 corresponded to an odds ratio of 1.84 (1.52–2.24) for EOCAD. The prevalence of a polygenic contribution that increased EOCAD risk similar to what is observed in heterozygous familial hypercholesterolemia was estimated at 1 in 53. In a local cohort of individuals with EOCAD (n=30), GRS182 was significantly increased compared with UK Biobank controls ( P =0.001). Seven participants (23%) had a GRS182 corresponding to an estimated 2-fold increase in EOCAD risk; none had a rare mutation involved in monogenic dyslipidemia or EOCAD. Conclusions These results suggest a significant polygenic contribution in individuals presenting with EOCAD, which could be more prevalent than familial hypercholesterolemia. Determination of the polygenic risk component could be included in the diagnostic workup of patients with EOCAD.

We report here detailed phylogenetic and comparative analyses on 11 sequenced genomes from the phylum Aquificae to identify molecular markers that are specific for the species from this phylum or its different families (viz. Aquificaceae, Hydrogenothermaceae and Desulfurobacteriaceae). In phylogenetic trees based on 16S rRNA gene or concatenated sequences for 32 conserved proteins, species from the three Aquificae families formed distinct clades. These trees also supported a strong relationship between the Aquificaceae and Hydrogenothermaceae families. In parallel, comparative analyses on protein sequences from Aquificae genomes have identified 46 conserved signature indels (CSIs) in broadly distributed proteins that are either exclusively or mainly found in members of the phylum Aquificae or its different families and subclades. Four of these CSIs, which are found in all sequenced Aquificae species, provide potential molecular markers for this phylum. Twelve, six and thirteen other CSIs that respectively are specific for the sequenced Aquificaceae, Hydrogenothermaceae and Desulfurobacteriaceae species provide molecular markers and novel tools for the identification of members of these families and for genetic and biochemical studies on them. Lastly, these studies have identified 11 CSIs in divergent proteins that are uniquely shared by members of the Aquificaceae and Hydrogenothermaceae families providing strong evidence that these two groups of bacteria shared a common ancestor exclusive of all other Aquificae (bacteria). The species from these two families are also very similar in their metabolic and physiological properties and they consist of aerobic or microaerophilic bacteria, which generally obtain energy by oxidation of hydrogen or reduced sulfur compounds by molecular oxygen. Based upon their strong association in phylogenetic trees, unique shared presence of large numbers of CSIs in different proteins, and similarities in their metabolic and physiological properties, it is proposed that the order Aquificales should be emended to include only the members of the families Aquificaceae and Hydrogenothermaceae. The members of the family Desulfurobacteriaceae, which are obligate anaerobes that strictly use hydrogen as electron donor, are now transferred to a new order Desulfurobacteriales ord. nov. The emended descriptions of the phylum Aquificae and its three families incorporating information for different molecular signatures are also provided.