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A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes. This work was funded by the National Institutes of Health (R01 HL127564 to S.K.), which had no involvement in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, and approval of the manuscript. This project was also conducted using the Type 2 Diabetes Knowledge Portal resource which is funded by the Accelerating Medicines Partnership. REGICOR study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research andTechnology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). NJS is supported by the British Heart Foundation and is a NIHR Senior Investigator. The Munich MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02).This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Vascular Biology (ATVB) Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010-2012 Area 1–Strategic Programmes– Diabetes Page 30 of 53 30 Regione Emilia-Romagna. Funding for the exome-sequencing project (ESP) was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Exome sequencing in ATVB, PROCARDIS, Ottawa, PROMIS, Southern German Myocardial Infarction Study, and the Jackson Heart Study was supported by 5U54HG003067 (to Dr. Gabriel).

Polygenic risk scores (PRSs) capture the polygenic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects individual9s disease risk, affording a new opportunity to identify downstream molecular pathways involved in disease pathogenesis. We performed an integrative analysis to characterise associations of PRSs of five cardiometabolic diseases with 3,442 plasma proteins in 3,175 healthy individuals. Through polygenic association scans we identified 48 plasma proteins whose levels were associated with PRSs for coronary artery disease (CAD), chronic kidney disease (CKD), or type 2 diabetes (T2D). This approach identified both well-known disease-associated proteins as well as those with previously no known link to these diseases. We found that PRSs to protein associations were largely truly polygenic; independent of single loci and genomic regions expected to have strong effects on protein levels. Our integrative analysis and laboratory experiments revealed a role for polygenic effects on several well-known disease proteins and identified several promising novel targets for follow-up studies, including genes which through Mendelian randomization analysis displayed causal evidence for effects on disease risk. Mouse studies highlighted specific tissues and phenotypes for PRS-associated human proteins. We found that implicated genes were responsive to dietary intervention in mice and showed strong evidence of druggability in humans, consistent with PRS-associated proteins having therapeutic potential. Overall, our study provides a framework for polygenic association studies, and demonstrates the power of polygenic scores to unravel novel disease biology.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia., Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

BackgroundCross-sectional studies of various forms of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin (‘TTNtv’) in 7-30% of patients, but the clinical importance of identifying a TTNtv in an asymptomatic adult is largely unknown. In contrast to cross-sectional studies, prospective cohort studies allow for unbiased estimates of the disease risks associated with a genotype exposure.ObjectivesTo determine the prevalence of cardiac imaging abnormalities and risk of incident disease among middle-aged TTNtv carriers without known congestive heart failure.MethodsWe analyze exome sequencing data of 45,747 participants of the UK Biobank without known congestive heart failure to identify TTNtv carriers. Among 10,552 with cardiac magnetic resonance imaging (MRI), we determine the relationship between TTNtv carrier status and left ventricular ejection fraction. In this prospective cohort, we quantify the absolute and relative risks of incident disease in TTNtv carriers versus noncarriers.ResultsAmong 45,747 middle-aged participants without known congestive heart failure, 196 (0.43%) harbored a TTNtv. The average ejection fraction was 61% in TTNtv carriers versus 65% in noncarriers (P = 1.8 × 10−8), with a 9.3-fold increase (95% CI 3.9 – 22.2) in odds of subnormal ejection fraction (P = 5.7 × 10−5). Over a median follow-up of 6.9 years, a composite endpoint of incident dilated cardiomyopathy, congestive heart failure, or all-cause mortality was observed in 6.6% of TTNtv carriers versus 2.9% of non-carriers (adjusted hazard ratio 2.5; 95% CI 1.4 – 4.3; p = 1.1 × 10−3).ConclusionsApproximately 1 in 230 middle-aged adults without known congestive heart failure harbored a TTNtv. These carriers had a substantially increased relative risk—but modest absolute risk—of having a subnormal ejection fraction or manifesting clinical disease during prospective follow-up.Condensed AbstractCross-sectional studies of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin (‘TTNtv’) in up to 30% of patients—but the clinical importance of TTNtv in asymptomatic adults is largely unknown. Here, we observe a TTNtv in 0.43% of 45,747 middle-aged adults. Average ejection fraction was 61% in TTNtv carriers versus 65% in non-carriers (p

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment. © 2019 Author(s), National Human Genome Research Institute (1K08HG0101), Wellcome Trust (202802/Z/16/Z), University of Bristol NIHR Biomedical Research Centre (S- BRC-1215-20011), National Human Genome Research Institute (HG008895), National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300025C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300026C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300027C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300028C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300029C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268200900041C, National Institute on Aging (AG0005), NHLBI (AG0005), National Human Genome Research Institute (U01-HG004729), National Human Genome Research Institute (U01-HG04424), National Human Genome Research Institute (U01-HG004446), Wellcome (102215/2/13/2)

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD. Dr Peloso is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number K01HL125751. Dr Nomura was supported by the Yoshida Scholarship Foundation. Dr Khera is supported by an institutional grant from the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard (BroadIgnite), a K08 from the National Human Genome Research Institute (K08HG010155), and a Junior Faculty Award from the National Lipid Association. Dr Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the NHLBI. Funding for the EOMI study (Exome Sequencing Project Early-Onset Myocardial Infarction) was provided by grants RC2 HL103010 (HeartGO, Heart Grand Opportunity), RC2 HL102923 (LungGO, Lung Grand Opportunity), and RC2 HL102924 (WHISP) from the NHLBI. Exome sequencing was performed through grants RC2 HL102925 (BroadGO, Broad Grand Opportunity) and RC2 HL102926 (SeattleGO, Seattle Grand Opportunity) from the NHLBI. Exome sequencing in ATVB (Italian Atherosclerosis, Thrombosis, and Vascular Biology), the PROCARDIS study (Precocious Coronary Artery Disease), the OHS (Ottawa Heart Study), PROMIS (Pakistan Risk of Myocardial Infarction Study), South German MI study (South German Myocardial Infarction), and the JHS (Jackson Heart Study) was supported by grant 5U54HG003067 from the National Institutes of Health. Fieldwork, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, European Union (EU) Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012–279233). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. REGICOR study (Registre Gironí del COR [Gerona Heart Registry]) was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester (Leicester Myocardial Infarction) cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The South MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces and SFB 1123. The ATVB study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010–2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. The authors would like to thank the MyCode Community Health Initiative participants for their permission to utilize their health and genomics information in the DiscovEHR (DiscovEHR partnership of the Regeneron Genetics Center and Geisinger Health System) collaboration. The DiscovEHR study was funded, in part, by the Regeneron Genetics Center.

Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10−8). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (−0.012 SD, 1.4*10−8), alkaline phosphatase (−0.019 SD, 6.6*10−9), total cholesterol (−0.037 SD, p=1*10−18) and LDL cholesterol (−0.035 SD, p=7.3*10−16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

An estimated 10% to 20% of youth in primary care exhibit behavioral symptoms and may go underdetected. Most screeners identify risk base of symptoms alone, irrespective of functional impairment. To address this issue, the Pediatric Symptom Checklist–17 (PSC-17), a widely used symptom screener, was combined with functional impairment and current behavioral services enrollment items to form the Pediatric Behavioral Health Screen (PBHS) and assessed compared to the full Child Behavior Checklist (CBCL). A total of 267 youth between 6 and 16 years of age were administered the screener and the CBCL. Areas under the receiver operating curves approached or exceeded 0.90 in all analyses, reflecting excellent classification accuracy. Almost no false negatives were observed among currently untreated cases with functional impairment. No differential item functioning was found. Performance of the PSC-17 as a pediatric primary care behavioral health screener supported previous research, and additional functional impairment items to form the PBHS appeared useful, particularly for interpreting borderline range scores.

Background: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201). Results: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci ( P –6 ), the majority linked to upstream HF risk factors, ie, coronary artery disease ( CDKN2B-AS1 and MAP3K7CL ) and atrial fibrillation ( PITX2 ). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy ( BAG3 , CLCNKA-ZBTB17 ). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P =3.62×10 –5 ). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (−0.09 SD, P = 3.4 × 10(−17)), Ile195Thr (−0.15 SD, P = 1.0 × 10(−9)), Ile482Val (−0.019 SD, P = 1.6 × 10(−5)), and rs72927479 (−0.035 SD, P = 2.6 × 10(−12)). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10(−13)). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.

Introduction: PAD is a leading cause of cardiovascular morbidity and mortality. Previously published GWAS have been limited by small sample sizes and have only identified 3 genome-wide significant (P-8 ) risk loci to date. Hypothesis: DNA sequence variants affecting multiple biological pathways are associated with PAD risk. Methods: Using electronic health record data, we identified individuals with and without clinical PAD from the 353,323 Million Veteran Program (MVP) participants genotyped on a customized Affymetrix Biobank array. We tested 32 million genotyped and imputed DNA variants for association with clinical PAD separately in participants of European (EUR), African (AFR), and Hispanic (HIS) ancestry using logistic regression models controlling for age, sex and population structure, and then performed trans-ethnic meta-analysis. The results were replicated with data from the UK Biobank. Results: We identified 31,307 individuals (24,009 EUR, 5,373 AFR, 1,925 HIS) with, and 211,753 individuals without, PAD. Following meta-analysis and replication, there were 19 genome-wide significant risk loci associated with PAD. We replicated a known association at 9p21 (P=4.3 x10 -39 ), and identified several novel loci associated with PAD that were previously known to be associated with atherosclerosis ( LPA , HDAC9 ), diabetes ( TCF7L2 ), lipid levels ( LPL , CELSR2 ), and tobacco use ( CHRNA3 ). We also identified a novel association with PAD for the Factor V Leiden (FVL) mutation (OR 1.20, P=1.6x10 -12 ), which remained significant after controlling for venous thromboembolism (OR 1.10, P=8.7x10 -4 ). Sensitivity analysis demonstrated FVL is associated with increasing risk estimates for PAD severity (claudication OR 1.19, P=0.0012; rest pain OR 1.41, P=0.004; tissue loss OR 1.57, P=7x10 -9 ). Conclusions: Using the MVP, we assembled the largest reported cohort of individuals with clinical PAD and genetic data worldwide. Our data replicate known causal risk factors and identify a novel association for FVL and its putative role for thrombosis in the development of clinical PAD.

Vascular inflammation drives the initiation and progression of coronary artery disease (CAD). However, the underlying genetic factors are not well understood. We performed a genome-wide association study in UK Biobank testing 9 million DNA variants for association with CAD (4,831 cases, 115,455 controls), followed by a meta-analysis with previous results. We identified ARHGEF26 (Rho guanine nucleotide exchange factor 26) as a novel locus significantly associated with CAD (combined OR=1.08, 95% CI 1.06-1.11, P=1.02 х 10 –9 ). We hypothesized that ARHGEF26 regulates vascular inflammation by affecting the function of vascular cells. Focusing on the haplotype tagged by the lead variant rs12493885 (ARHGEF26 p.Val29Leu), we performed eQTL and allele-specific expression analyses. There is no significant ARHGEF26 transcription alteration or allelic imbalance associated with the risk allele in human coronary artery samples. Promoter luciferase assay showed no significant difference between the reference and alternative haplotypes. In contrast, expression of exogenous Leu29 mutant after depletion of endogenous ARHGEF26 led to rescued phenotypes consistently exceeding those observed with overexpression of wild-type ARHGEF26, including increased leukocyte transendothelial migration, leukocyte adhesion on endothelial cells, and smooth muscle cell proliferation. These data suggest that the CAD-risk allele (Leu29) may lead to a gain of protein function in vascular cells. To identify the molecular mechanism, we compared the nucleotide-exchange activity between the wild-type and mutant proteins and found no significant difference. Evaluation of ARHGEF26 protein stability by cycloheximide chase showed the Leu29 mutant displayed longer half-life than wild-type ARHGEF26, suggesting the gain-of-function phenotypes of Leu29 in cells may be secondary to its resistance to degradation. Quantitative proteomics revealed differential protein interaction between the wild-type and Leu29 ARHGEF26 in endothelial cells, highlighting critical inflammatory pathways impacted by the CAD-risk allele. In summary, our work identified a novel genetic risk factor for CAD, and enabled discovery of novel CAD-causing pathways in vascular inflammation.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency, Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

Families experiencing child maltreatment or risk factors for child maltreatment often receive referrals to interventions focused on changing parenting practices. Compliance with specific parenting programs can be challenging as many of the stressors that place families at-risk may also interfere with program participation. Because families may receive limited benefit from programs they do not fully receive, it is critical to understand the relationship between parenting stress and barriers to program completion. We used structural equation modeling to examine the relationship among parenting stress, perceived barriers to program participation, and program completion in two datasets involving low-income parents. Data were collected at two time points from a sample of parents involved with child welfare services and a sample of parents considered at-risk of future involvement (total study n = 803). Direct paths from parenting stress at time 1 to barriers to participation and parenting stress at time 2, and from parenting stress at time 2 to program completion were significant. Interestingly, increased barriers to participation were related to increased parenting stress at time 2, and greater parenting stress was related to increased program completion. Results suggest that with increasing levels of parenting stress, parents have an increased likelihood of completing the program. Assessing and addressing the influence of perceived barriers and parenting stress on program participation may decrease the likelihood of treatment attrition.

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation 1 . Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature 2–5 , it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk 6 . We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Background— Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified. Methods and Results— We assessed the contribution of genome-wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, h 2 g ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated h 2 g using a variance components method with variants having a minor allele frequency ≥1%. We evaluated h 2 g in age, sex, and genomic strata of interest. The h 2 g for AF was 22.1% (95% confidence interval, 15.6%–28.5%) and was similar for early- versus older-onset AF (≤65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, ≥5%) variants (20.4%; 95% confidence interval, 15.1%–25.6%). Only 6.4% (95% confidence interval, 5.1%–7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions. Conclusions— Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.

This article presents the American Professional Society on the Abuse of Children (APSAC) Task Force report on the evidence-based service planning (EBSP) approach to child welfare services (CWS) plans and recommendations for practice. The focus of the policy report is on formal psychosocial services. CWS plans prescribe services to promote core child welfare objectives and to benefit children and families. The goal of EBSP is to construct service plans based on the general principles of evidence-based practice and prefer services with empirical support for clinical problems or needs associated with the causes or consequences of child abuse and neglect (CAN). EBSP aims to facilitate an overarching service approach that is collaborative, respectful, and includes services that are most likely to lead to outcomes on both family identified and child welfare mission goals. EBSP emphasizes a focused, assessment-driven, and science-informed approach that both favors plans that are sufficient and avoids overburdening families with compulsory services that address problems which are not directly related to the child welfare CAN referral.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle where apolipoprotein(a) (protein product of theLPAgene) is covalently attached to apolipoprotein B. Lp(a) is a highly heritable, causal risk factor for cardiovascular diseases and varies in concentrations across ancestries. To comprehensively delineate the inherited basis for plasma Lp(a), we performed deep-coverage whole genome sequencing in 8,392 individuals of European and African American ancestries. Through whole genome variant discovery and direct genotyping of all structural variants overlappingLPA, we quantified the 5.5kb kringle IV-2 copy number (KIV2-CN), a knownLPAstructural polymorphism, and developed a model for its imputation. Through common variant analysis, we discovered a novel locus (SORT1) associated with Lp(a)-cholesterol, and also genetic modifiers of KIV2-CN. Furthermore, in contrast to previous GWAS studies, we explain most of the heritability of Lp(a), observing Lp(a) to be 85% heritable among African Americans and 75% among Europeans, yet with notable inter-ethnic heterogeneity. Through analyses of aggregates of rare coding and non-coding variants with Lp(a)-cholesterol, we found the only genome-wide significant signal to be at a non-codingSLC22A3intronic window also previously described to be associated with Lp(a); however, this association was mitigated by adjustment with KIV2-CN. Finally, using an additional imputation dataset (N=27,344), we performed Mendelian randomization ofLPAvariant classes, finding that genetically regulated Lp(a) is more strongly associated with incident cardiovascular diseases than directly measured Lp(a), and is significantly associated with measures of subclinical atherosclerosis in African Americans.

Identification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

The number of HIV cases attributed to heterosexual contact and the proportion of women among HIV positive individuals has increased worldwide. Russia is a country with the highest rates of newly diagnosed HIV infections in the region, and the infection spreads beyond traditional risk groups. While young women are affected disproportionately, knowledge of HIV risk behaviors in women in the general population remains limited. The objectives of this study were to identify patterns of behaviors that place women of childbearing age at high risk for HIV transmission and determine whether socio-demographic characteristics and alcohol use are predictive of the risk pattern. A total of 708 non-pregnant women, aged between 18–44 years, who were at risk for an alcohol-exposed pregnancy (AEP) were enrolled in two regions in Russia. Participants completed a structured interview focused on HIV risk behaviors, including risky sexual behavior and alcohol and drug use. Latent class analysis was utilized to examine associations between HIV risk and other demographic and alcohol use characteristics and to identify patterns of risk among women. Three classes were identified. 34.93% of participants were at high risk, combining their risk behaviors, e.g., having multiple sexual partners, with high partner's risk associated with partner's drug use (class I). Despite reporting self-perceived risk for HIV/STI, this class of participants was unlikely to utilize adequate protection (i.e., condom use). The second high risk class included 13.19% of participants who combined their risky sexual behaviors, i.e., multiple sexual partners and having STDs, with partner's risk that included partner's imprisonment and partner's sex with other women (class II). Participants in this class were likely to utilize protection/condoms. Finally, 51.88% of participants were at lower risk, which was associated primarily with their partners' risk, and these participants utilized protection (class III). The odds of being in class I compared with class III were 3.3 (95% CI: [1.06, 10.38]) times higher for those women who had Alcohol Use Disorders Identification Test scores ≥8 than those who had lower scores, and were 3.9 (95% CI: [1.69, 8.97]) times higher for those who used alcohol before sex than those who did not. In addition, women who drank more days per week were 1.36 times more likely to be in class II than in class III. The study informs prevention by identifying specific population groups and targets for interventions. Alcohol use is a significant predictor and an overarching factor of HIV risk in women. Since at-risk drinking is common among young Russian women, alcohol risk reduction should be an essential component of HIV prevention efforts.

Early home visitation (EHV) for child maltreatment prevention is widely adopted but has received inconsistent empirical support. Supplementation with interactive software may facilitate attention to major risk factors and use of evidence-based approaches. We developed eight 20-min computer-delivered modules for use by mothers during the course of EHV. These modules were tested in a randomized trial in which 413 mothers were assigned to software-supplemented e-Parenting Program ( ePP), services as usual (SAU), or community referral conditions, with evaluation at 6 and 12 months. Outcomes included satisfaction, working alliance, EHV retention, child maltreatment, and child maltreatment risk factors. The software was well-received overall. At the 6-month follow-up, working alliance ratings were higher in the ePP condition relative to the SAU condition (Cohen's d = .36, p < .01), with no differences at 12 months. There were no between-group differences in maltreatment or major risk factors at either time point. Despite good acceptability and feasibility, these findings provide limited support for use of this software within EHV. These findings contribute to the mixed results seen across different models of EHV for child maltreatment prevention.

Russia has one of the fastest rising rates of HIV among women in the world. This study sought to identify key factors in HIV transmission among women in Russia. Data were collected as part of a larger clinical trial to prevent alcohol-exposed pregnancies (AEP). Women at risk for an AEP were recruited at women’s clinics; 708 women, aged 18 – 44 (M= 29.04 years), completed HIV risk surveys. Structural Equations Modeling (SEM) was used to test the relationships between alcohol use and sex behavior constructs with HIV/STI risk. While the model indicated that multiple factors are involved in women’s HIV/STI risk, the independent alcohol use variable explains 20% of the variance in women’s HIV/STI risk. The findings suggest that alcohol use directly and indirectly predicts HIV/STI risk among women, and its effect is mediated by alcohol use before sex.

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery(8).

Clinical and epidemiological data suggest that asthma and allergic diseases are associated and may share a common genetic etiology. We analyzed genome-wide SNP data for asthma and allergic diseases in 33,593 cases and 76,768 controls of European ancestry from UK Biobank. Two publicly available independent genome-wide association studies were used for replication. We have found a strong genome-wide genetic correlation between asthma and allergic diseases (rg = 0.75, P = 6.84 × 10−62). Cross-trait analysis identified 38 genome-wide significant loci, including 7 novel shared loci. Computational analysis showed that shared genetic loci are enriched in immune/inflammatory systems and tissues with epithelium cells. Our work identifies common genetic architectures shared between asthma and allergy and will help to advance understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases. Genome-wide cross-trait analysis shows a strong genetic correlation between asthma and allergic diseases. Shared susceptibility loci are enriched for genes involved in immune and inflammatory responses and genes expressed in epithelial tissues.

Families living in poverty are significantly more likely to become involved with child welfare services, and consequently, referred to interventions that target abusive and neglectful parenting practices. Program engagement and retention are difficult to achieve, possibly because of the concrete resource insufficiencies that may have contributed to a family's involvement with services in the first place. Various strategies have been used to enhance program completion, such as motivational interventions, monetary incentives, and financial assistance with concrete needs. This study examines the influence of adjunctive concrete support provided by home visitors on families' (N = 1754) engagement, retention, and satisfaction with services as well as parenting outcomes. Using propensity stratification, mixed modeling procedures revealed that increasing concrete support predicted greater engagement, satisfaction, goal attainment, and lower short-term recidivism. Results suggest that adjunctive concrete support is a potentially beneficial strategy for promoting service engagement and satisfaction and increasing short-term child safety.

Background: Atrial fibrillation (AF) is a common and heritable arrhythmia associated with substantial morbidity. Previous reports have implicated over 30 genes and 16 loci in the pathogenesis of AF, but the genetic architecture of the arrhythmia has not been systematically characterized. Methods: We assessed AF heritability in 120,286 unrelated individuals of European ancestry (2,981 with AF) from the population-based UK Biobank. We ascertained AF based on self-reported disease history and/or billing codes from medical record data. To validate the phenotype definition, we examined genetic associations with AF for variants at known susceptibility loci reported in prior independent genome-wide association studies. We then estimated the proportion of AF variance explained by additive genetic variation (heritability) using a variance components method (BOLT-REML) based on ~800,000 independent high quality imputed variants with minor allele frequencies (MAF) ≥ 1%. We further evaluated the heritability of AF by sex, allele frequency, and established AF loci from association studies (+/- 500 kb of a top associated variant). All analyses were adjusted for baseline age, sex, array, and 15 principal components of ancestry. Results: The average age was higher in AF cases than in referents (62.3 years vs. 56.8 years), and more AF cases were male (69% vs. 47%). We observed expected associations between genetic variation and AF, validating our AF definition. The heritability of AF was 22.3% (95% confidence interval [CI] 15.8%-28.8%), and no substantive difference was observed between males and females. We observed that the AF variance was mainly explained by common variants with MAF ≥ 5% (20.6%, 95%CI 15.2%-25.9%) rather than low-frequency variants with MAF between 1%- Conclusions: Using a population-based sample of European ancestry, we observed that a substantial proportion of variance in AF risk is attributable to additive genetic variation. AF variance is predominantly accounted for by common variants. Only a small proportion of AF variance is attributable to known AF loci. Our findings suggest that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.

UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry. We performed a genome-wide association study in UK Biobank testing ∼9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes.

Posttraining expert case consultation is a key component of transporting and scaling up evidence-based treatments, and hopefully retaining their efficacy. Live practice observation and in vivo coaching is a strategy used in academic training environments, but is rarely feasible in field settings. Post hoc telephone consultation is a substitute strategy but does not approximate many aspects of live coaching. Live video technology offers a closer approximation but has not yet been sufficiently tested. Using a roll-out experimental design, this study compared client outcomes across doses of two posttraining expert consultation strategies-standard telephone consultation and live video coaching. The study was conducted during a two-state, 30-agency implementation involving 80 therapists and 330 cases receiving Parent-Child Interaction Therapy (PCIT). Child behavior problems fell from well above to below clinical cutoff values, with about a 1 standard deviation improvement in 14 sessions, which is within the range reported in laboratory efficacy trials. Symptom improvement was augmented by increased therapist dose of live video consultations. Phone consultation dose had no association with client level outcomes. PCIT benefits appear to be retained when the model is transported at scale into the field, and live video consultation appeared to offer small but significant advantages over telephone consultation as one element of an overall transport strategy.

Background System-wide scale up of evidence-based practice (EBP) is a complex process. Yet, few strategic approaches exist to support EBP implementation and sustainment across a service system. Building on the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework, we developed and are testing the Interagency Collaborative Team (ICT) process model to implement an evidence-based child neglect intervention (i.e., SafeCare®) within a large children's service system. The ICT model emphasizes the role of local agency collaborations in creating structural supports for successful implementation. Methods We describe the ICT model and present preliminary qualitative results from the use of the implementation model in one large scale EBP implementation. Qualitative interviews were conducted to assess challenges in building system, organization, and home visitor collaboration and capacity to implement the EBP. Data collection and analysis centered on EBP implementation issues, as well as the experiences of home visitors under the ICT model. Results Six notable issues relating to implementation process emerged from participant interviews, including: (a) initial commitment and collaboration among stakeholders, (b) leadership, (c) communication, (d) practice fit with local context, (e) ongoing negotiation and problem solving, and (f) early successes. These issues highlight strengths and areas for development in the ICT model. Conclusions Use of the ICT model led to sustained and widespread use of SafeCare in one large county. Although some aspects of the implementation model may benefit from enhancement, qualitative findings suggest that the ICT process generates strong structural supports for implementation and creates conditions in which tensions between EBP structure and local contextual variations can be resolved in ways that support the expansion and maintenance of an EBP while preserving potential for public health benefit.

Implementation and scale-up of evidence-based practices (EBPs) is often portrayed as involving multiple stakeholders collaborating harmoniously in the service of a shared vision. In practice, however, collaboration is a more complex process that may involve shared and competing interests and agendas, and negotiation. The present study examined the scale-up of an EBP across an entire service system using the Interagency Collaborative Team approach. Participants were key stakeholders in a large-scale county-wide implementation of an EBP to reduce child neglect, SafeCare. Semistructured interviews and/or focus groups were conducted with 54 individuals representing diverse constituents in the service system, followed by an iterative approach to coding and analysis of transcripts. The study was conceptualized using the Exploration, Preparation, Implementation, and Sustainment framework. Although community stakeholders eventually coalesced around implementation of SafeCare, several challenges affected the implementation process. These challenges included differing organizational cultures, strategies, and approaches to collaboration; competing priorities across levels of leadership; power struggles; and role ambiguity. Each of the factors identified influenced how stakeholders approached the EBP implementation process. System-wide scale-up of EBPs involves multiple stakeholders operating in a nexus of differing agendas, priorities, leadership styles, and negotiation strategies. The term collaboration may oversimplify the multifaceted nature of the scale-up process. Implementation efforts should openly acknowledge and consider this nexus when individual stakeholders and organizations enter into EBP implementation through collaborative processes.

Familial hypobetalipoproteinemia (FHBL) is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding apolipoprotein B (APOB), the major protein component of low-density and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with

Importance Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, setting, and participants The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main outcomes and measures Early-onset AF (defined as AF onset in persons Results Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). Conclusions and relevance In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

The extent evidence-based treatments (EBTs) are used in clinical practice within the Australian therapeutic child welfare sector is unknown. In this study, we investigated practitioners' knowledge, attitudes, and use of EBT when providing interventions to children and families and how the intended outcomes of interventions are evaluated. Practitioners (N = 112) from 41 non-government organizations were surveyed and reported few barriers to implementing EBTs and positive attitudes. While just over half the practitioners surveyed provided an accurate definition of EBT, 72 % of practitioners reported using EBTs in their clinical practice. Of those, 88 % reported modifying the EBT, however interventions were rarely evaluated systematically. Implications for the use of EBTs, how they are modified, and the role of systematic evaluation are discussed.

Parent training programs are the most common type of service prescribed for parents in the child welfare system. Parent-Child Interaction Therapy (PCIT), an evidence-based model originally developed as a parent-mediated treatment for disruptive behavior problems in preschool-age children, has been adapted as an intervention for maltreating parents of preschool- and school-age children. PCIT uses behavioral principles to: (a) increase positive parenting skills; (b) enhance the parent-child relationship; (c) establish effective and consistent behavior management strategies; and (d) decrease child behavior problems. The adapted version of PCIT for child welfare populations includes a motivational enhancement component which has been found necessary for reducing child welfare recidivism. Additional PCIT research findings indicate significant improvements in mental health and behavior among children in the child welfare system. The PCIT model is flexible and has been extended to home-based services and foster care settings. The fact that PCIT robustly delivers two types of benefits (i.e. reduced recidivism risk among abusive parents and improved wellbeing and behavior among children) in one compact and focused intervention makes it particularly appealing for child welfare service systems. This chapter describes PCIT and the adaptations that have been made for use in child welfare. The chapter also addresses cross-cultural adaptations of PCIT and summarizes some barriers and related implementation strategies.

Objective of this study is to identify background infant and maternal characteristics that predict child maltreatment (CM) incidence reporting among Neonatal Intensive Care Unit (NICU) graduates by health care providers versus community sentinels with the goal of identifying ways to improve CM risk surveillance. Demographic, medical data including diagnoses and caregiving needs at discharge for infants treated in a NICU during 2005 to 2008 were obtained from the neonatology databases. CM outcome data was obtained from child welfare databases. Latent class analysis procedures were used to identify observable infant and maternal characteristics that define unobserved groups (latent classes) that predict NICU graduates CM incidence reporting among health care providers versus community sentinels. Medical surveillance (reports made by health care providers) accounted for only 37% of the CM reports made to child welfare. Infant health was more predictive of medical surveillance than maternal characteristics suggesting that health providers may assess risk differently than community sentinels. Based on a simple, two latent class model, the latent class with high infant health indicator membership probabilities was a better predictor of health care provider related reports than the class with lower membership probabilities (odds ratio = 2.72; 95% confidence interval [1.76, 4.20]). Health care providers may be keyed more to an infant's medical frailty than to caregiver (maternal) contextual characteristics and thus may miss an opportunity to identify and intervene to prevent CM among children with medical problems. Findings raise the question of whether increased attention to contextual factors can aid or increase early identification of infants at risk of child maltreatment in NICU settings.

Drinking patterns among Russian women indicate substantial risk for alcohol-exposed pregnancies. Data about women's knowledge and attitudes related to alcohol consumption during pregnancy and the extent to which women's knowledge and attitudes affect their alcohol use remain limited.To describe Russian women's knowledge and attitudes and assess whether women's knowledge and attitudes were associated with their risky drinking.A cross-sectional survey was administered to women of childbearing age (n = 648). Participants were recruited at women's health clinics and asked about their alcohol consumption, pregnancy status, attitudes, and knowledge about effects of alcohol and Fetal Alcohol Syndrome (FAS).40% of the women surveyed believed or were uncertain whether alcohol consumption during pregnancy was acceptable. Although 34% had heard of FAS, only 8% possessed accurate knowledge. Correct knowledge was associated with decreased alcohol consumption among pregnant women, but there was no association between knowledge and risky drinking in nonpregnant women, including those who were at risk for an unplanned pregnancy or were trying to conceive. However attitudes were strongly associated with risky drinking by nonpregnant women across levels of knowledge about FAS and any alcohol use by pregnant women.Russian women had limited knowledge and several misconceptions about the effects of alcohol on the fetus, and risky alcohol consumption was strongly associated with women's attitudes and knowledge. The study provides strong evidence to support continuing public health education about effects of alcohol use during pregnancy. Correcting specific misconceptions and targeting the preconceptional period in health communications are necessary to reduce at-risk drinking and the risk for alcohol-exposed pregnancies.

Few studies have specifically examined prevention of child maltreatment among higher-risk populations in rural communities. The overarching goal of this study was to conduct a randomized clinical trial of SafeCare augmented for rural high-risk population (SC+) compared to standard home-based mental health services (SAU) to examine reductions in future child maltreatment reports, as well as risk factors and factors proximal to child maltreatment. Parents (N = 105) of young children (5 years or less) who had identifiable risk of depression, intimate partner violence, or substance abuse were randomized to SC+ or SAU. Participants randomized to SC+ were more likely to enroll (83% vs. 35% for SAU) and remain in services (35 h vs. 8 h for SAU). SC+ (for participants who successfully completed services) may have had limited impact on child welfare reports during service provision. Further, SC+ had fewer child welfare reports related to DV than SAU. Parent self-reports of parenting behaviors, risk factors, and protective factors did not demonstrate significant sustained program impact. Limitations include power constraints related to sample size. Promising next steps entail future trials with larger sample sizes examining service compliance and further augmentation of SafeCare to bolster service impact and address risk and protective factors.

OBJECTIVES: Parental depression symptoms often change over the course of child welfare family preservation and parenting services. This raises the question of whether certain processes in family preservation services might be associated with depression symptom change. This study tests three correlational models of change among family preservation service participants: (a) changes in depression symptoms are one facet of broad general changes in wellbeing; (b) the quality of the home visitor-client relationship is associated depression symptom changes; and (c) linking parents to adjunctive services is associated with symptom changes. METHODS: Participants were 2,175 parents in family preservation services, largely for child neglect, who were surveyed using standard measures at pre-treatment, post-treatment and 6 month follow-up. Change patterns were evaluated using growth models, including bivariate parallel and multivariate second-order models. RESULTS: Parallel growth was noted among depression symptoms and changes in social, economic, familial, and parenting domains. A second order change model positing a global change pattern fit the data well. Working alliance had a modest association with improvement, but successful linkage to outside mental health services was not associated with improvement. CONCLUSIONS: Changes in diverse indicators of wellbeing follow a global pattern which might support use of less complex rather than more fully comprehensive service plans. Findings about lack of adjunctive usual care mental health service benefit may be related to uncontrolled factors and this is a topic in need of additional study. Language: en

This study examines how risk factor change patterns vary with case chronicity, and whether risk factor improvement still predicts lower recidivism risk among chronic cases. 2,175 parents in home based child welfare services were surveyed for risk factors at pre-treatment, post-treatment and 6-month follow-up. Mixture modeling of latent difference scores identified change trajectory classes related retrospectively to chronicity and prospectively to recidivism. Five change trajectories were identified: stable low problem, stable high problem, sustained improvement, relapsing, and paradoxical. Chronicity was associated with a decreasing probability of membership in the stable low problem trajectory and increasing probability of membership in the stable high problem and sustained improvement trajectories. Cases with more favorable trajectories recidivated less across levels of chronicity. Findings suggest that chronic cases may improve little, but still retain a stable or increasing chance of sustained improvement associated with lower risk. A cumulative service benefit might be one possible explanation for this observation, and might suggest that repeated intervention efforts are not always wasted on chronic cases. The current episodic and reactive service delivery model in child welfare may be a mismatch with chronic cases where progress is absent or tends to occur cumulatively across service episodes.

Objective: A package of parent–child interaction therapy (PCIT) combined with a self-motivational (SM) orientation previously was found in a laboratory trial to reduce child abuse recidivism compared with services as usual (SAU). Objectives of the present study were to test effectiveness in a field agency rather than in a laboratory setting and to dismantle the SM versus SAU orientation and PCIT versus SAU parenting component effects. Method: Participants were 192 parents in child welfare with an average of 6 prior referrals and most with all of their children removed. Following a 2 2 sequentially randomized experimental design, parents were randomized first to orientation condition (SM vs. SAU) and then subsequently randomized to a parenting condition (PCIT vs. SAU). Cases were followed for child welfare recidivism for a median of 904 days. An imputation-based approach was used to estimate recidivism survival complicated by significant treatment-related differences in timing and frequency of children returned home. Results: A significant orientation condition by parenting condition interaction favoring the SM PCIT combination was found for reducing future child welfare reports, and this effect was stronger when children were returned to the home sooner rather than later. Conclusions: Findings demonstrate that previous laboratory results can be replicated in a field implementation setting and among parents with chronic and severe child welfare histories, supporting a synergistic SM PCIT benefit. Methodological considerations for analyzing child welfare event history data complicated by differential risk deprivation are also emphasized.

In the version of this article originally published, there were two errors in the text of the second paragraph of the Methods section. In the sentence “To identify genetic variants that contribute to doctor-diagnosed asthma and allergic diseases (detailed phenotype information described in the Supplementary Note) and link them with other conditions, we performed GWASs using phenotype measures in UK Biobank participants (N = 487,409)” the number of participants should have been 150,509. In the sentence “Thus, a total of 110,361 European descendants with high-quality genotyping and complete phenotype/covariate data were used for these analyses, including 25,685 allergic diseases subjects (hay fever/allergic rhinitis or eczema, without doctor-diagnosed asthma), 14,085 asthma subjects and 76,768 controls for the analysis” the phrase “without doctor-diagnosed asthma” should have read “some with doctor-diagnosed asthma.” The errors have been corrected in the HTML and PDF versions of the article.

Objective Parent-child interaction therapy (PCIT) has been found to reduce future child abuse reports among physically abusive parents. Reductions in observed negative parenting behaviors mediated this benefit. The current study examined session-by-session interaction sequences in order to identify when during treatment these changes occur and how much the trajectory varies from case-to-case. Method Session-by-session parent-child interaction sequences, using the Dyadic Parent-Child Interaction Coding System-II (DPICS-II) categories, were coded for 22 child welfare involved parent-child dyads undergoing PCIT for child physical abuse. A total 5,436 interactions across PCIT were coded and analyzed using growth curve analysis. Results At pre-treatment baseline, negative and positive parental responses were about equally likely to follow a child positive behavior. This pattern changed rapidly during PCIT, with rapid increases in positive parental responses and decreases in negative parental responses to appropriate child behavior. A quadratic growth pattern accounted for 70% of observed variance and virtually all change occurred during the first three sessions. Conclusion Changes in observed abusive parent-abused child interaction patterns can occur early in PCIT, a parenting intervention that involves direct coaching and practice of skills. These benefits sustained throughout treatment. Practice implication Prior to receiving behavioral parent training (PCIT), parents who have physically abused their children failed to match their parental response to their children's behavior. This pattern of interaction improved rapidly and substantially during the first three sessions of PCIT. The changes in the patterns of interaction also remained relatively stable for the remainder of treatment while parents continued to practice positive parental responses as well as began practicing effective discipline techniques. This suggests that use of immediate parent feedback through coaching, explicit directions to parents in how to respond to child behavior, and customization of the application of skills to the problems that arise in session are important components to effective parenting programs with physically abusive parents. Targeting these behaviors with PCIT has been found to reduce rates of recidivism, further supporting clinical application of PCIT in these cases.