Prevalence and correlates of anxiety and depressive symptoms after Spontaneous Coronary Artery Dissection (SCAD): a cross-sectional study.

AIMS: Spontaneous coronary artery dissection (SCAD) is recognised as a particularly stressful cause of heart attack. However few studies have documented the prevalence of post-SCAD anxiety and depressive symptoms, or identified patients most at risk. This study documents the prevalence and correlates of post-SCAD anxiety and depressive symptoms. METHOD AND RESULTS: 310 (95% women) SCAD survivors were recruited by the Victor Chang Cardiac Research Institute from a database of 433 SCAD survivors. Participants completed an online questionnaire to gather demographic, medical and psychosocial information, including the Generalised Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Bivariate and multivariate analyses were undertaken to identify the significant demographic, psychosocial and medical correlates of post-SCAD anxiety and depressive symptoms. Time between SCAD and questionnaire completion varied from 2 months to 18 years (mean = 5.5 years; SD = 3.5 years). Rates of anxiety and depressive symptoms were 20.7% (GAD-7 ≥ 10) and 20.9% (PHQ-9 ≥ 10) respectively, and did not vary by time since event. In bivariate analyses, correlates (p < .05) of anxiety and depressive symptoms were absence of a close confidante, financial strain, mental health diagnosis pre-SCAD, comorbid obesity, not being in paid employment (anxiety only), younger age (depression only), and not knowing another SCAD survivor (depression only). Variables retained in multivariate models were absence of a close confidante, financial strain, not being in paid employment, mental health diagnosis pre-SCAD (depression only), and younger age (depression only). CONCLUSION: This study demonstrated that over one in four SCAD survivors experience either anxiety or depressive symptoms after SCAD, and identified those who may need additional support in their psychological recovery.

Psychosocial and lifestyle impacts of spontaneous coronary artery dissection: A quantitative study.

INTRODUCTION: Recent studies suggest that acute myocardial infarction due to spontaneous coronary artery dissection (SCAD) carries significant psychosocial burden. This survey-based quantitative study builds on our earlier qualitative investigation of the psychosocial impacts of SCAD in Australian SCAD survivors. The study aimed to document the prevalence and predictors of a broad range of psychosocial and lifestyle impacts of SCAD. METHOD: Australian SCAD survivors currently enrolled in the Victor Chang Cardiac Research Institute genetics study were invited to participate in an online survey to assess the psychosocial impacts of SCAD. Participants completed a questionnaire, developed using findings from our earlier qualitative research, which assessed 48 psychosocial and five lifestyle impacts of SCAD. Participants also provided demographic and medical data and completed validated measures of anxiety and depression. RESULTS: Of 433 SCAD survivors invited to participate, 310 (72%) completed the questionnaire. The most common psychosocial impacts were 'shock about having a heart attack' (experienced by 87% respondents), 'worry about having another SCAD' (81%), 'concern about triggering another SCAD' (77%), 'uncertainty about exercise and physical activity' (73%) and 'confusion about safe levels of activity and exertion' (73.0%) and 'being overly aware of bodily sensations' (73%). In terms of lifestyle impacts, the SCAD had impacted on work capacity for almost two thirds of participants, while one in ten had sought financial assistance. The key predictors of psychosocial impacts were being under 50, current financial strain, and trade-level education. The key predictors of lifestyle impacts were being over 50, SCAD recurrence, trade-level education, and current financial strain. All psychosocial impacts and some lifestyle impacts were associated with increased risk of anxiety and/or depression. CONCLUSION AND IMPLICATIONS: This quantitative study extends our previous qualitative investigation by documenting the prevalence of each of 48 psychosocial and five lifestyle impacts identified in our earlier focus group research, and by providing risk factors for greater SCAD impacts. The findings suggest the need for supports to address initial experiences of shock, as well as fears and uncertainties regarding the future, including SCAD recurrence and exercise resumption. Support could be targeted to those with identified risk factors. Strategies to enable SCAD survivors to remain in or return to the paid workforce are also indicated.

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective: To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls. Design, Setting, and Participants: This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023. Exposures: PRS for SCAD comprised of 7 single-nucleotide variants. Main Outcomes and Measures: Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS. Results: A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10-4; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10-4). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes. Conclusions and Relevance: Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

Generation of induced pluripotent stem cell lines from a sister pair who suffered post-partum or recurrent Spontaneous Coronary Artery Dissections.

Spontaneous Coronary Artery Dissection (SCAD) results from a bleed within a coronary artery wall that impairs blood flow as it expands. It is the most common cause of myocardial infarction in pregnant women. Here, peripheral blood mononuclear cells from two sisters who had suffered SCADs were reprogrammed using Sendai Virus. Expression of pluripotency markers, capability to differentiate to the three germ layers, and cellular integrity were confirmed. This is the first report of a SCAD family induced pluripotent stem cell (iPSC) cohort, including a sister who suffered post-partum SCAD, and one who suffered from multiple recurrences.

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Prevalence of Anxiety, Depression, and Distress in SCAD and Non-SCAD AMI Patients: A Comparative Study.

PURPOSE: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute myocardial infarction (AMI), particularly in younger women without classic cardiac risk factors. Spontaneous coronary artery dissection is considered to be particularly stressful; however, few studies have quantified SCAD survivor stress levels. This study compared anxiety, depression, and distress levels in SCAD and non-SCAD AMI patients. METHOD: A sample of 162 AMI (35 [22%] SCAD) patients was recruited from hospitals and via social media, in Australia and the United States. All had had their AMI in the past 6 mo. Participants completed an online questionnaire comprising the Generalized Anxiety Disorder-2 (GAD2), Patient Health Questionnaire-2 (PHQ2), Kessler-6 (K6), and Cardiac Distress Inventory (CDI). T-tests, χ 2 tests, Mann-Whitney tests, and analysis of covariance were used to compare SCAD and non-SCAD samples. Logistic regression was used to identify the unique predictors of anxiety, depression, and distress, controlling for relevant confounders. RESULTS: Patients with SCAD were more commonly female and significantly younger than non-SCAD patients. Patients with SCAD scored significantly higher on the GAD2, PHQ2, K6, and CDI and a significantly larger proportion was classified as anxious, depressed, or distressed using these instruments. In logistic regression, together with mental health history, having had a SCAD-AMI predicted anxiety, depression, and distress, after controlling for female sex, younger age, and other confounding variables. CONCLUSION: This study supports the view that anxiety, depression, and distress are more common after SCAD-AMI than after traditional AMI. These findings highlight the psychosocial impacts of SCAD and suggest that psychological support should be an important component of cardiac rehabilitation for these patients.

Psychosocial impacts of spontaneous coronary artery dissection: A qualitative study.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute myocardial infarction, particularly in younger women without classic cardiac risk factors. While recent quantitative studies have noted high anxiety and depression in SCAD survivors, the full range and extent of psychosocial impacts of SCAD is unknown. The present study used a qualitative approach to investigate the psychosocial impacts of SCAD in Australian SCAD survivors. Focus group participants were recruited as part of a larger study of SCAD survivors currently being undertaken by the Victor Chang Cardiac Research Institute. Thirty SCAD survivors participated in one of seven online focus groups, conducted using a semi-structured format. Focus group duration was 1.5 hours. Each was digitally recorded and transcribed. Data were analyzed thematically according to recommended guidelines. One over-arching theme, five main themes and 26 sub-themes were identified. The over-arching theme related to lack of information, while the five main themes related to emotional impacts, issues with self-management, issues with family, impacts on work life, and the need for psychosocial support. The 'emotional impacts' theme comprised 11 sub-themes, namely shock and disbelief, confusion and uncertainty, unfairness, fear and anxiety, loss and grief, isolation and loneliness, guilt, invalidation and embarrassment, depression, vulnerability, and frustration. Findings are discussed in light of relevant psychological theories. This qualitative study extends previous quantitative investigations of SCAD survivors by providing an in-depth understanding of the complex, inter-related and highly distressing impacts of SCAD. The findings point to the urgent need for a coherent approach to information provision, the development and delivery of SCAD-specific cardiac rehabilitation programs, and the provision of psychosocial support programs for SCAD survivors.

Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. METHODS: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. RESULTS: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-ß signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. CONCLUSIONS: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.

Spontaneous Coronary Artery Dissection and Fibromuscular Dysplasia: Vasculopathies With a Predilection for Women.

The burden of cardiovascular disease in women is being increasingly appreciated. Nevertheless, both clinicians and the general public are largely unaware that cardiovascular disease is the leading cause of death worldwide in women in all countries and that outcomes after a heart attack are worse for women than men. Of note, certain types of cardiovascular disease have a predilection for women, including spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). Although uncommon, SCAD is being increasingly recognised as the cause of an acute coronary syndrome (ACS) and can recur. It is a potentially fatal, under-diagnosed condition that affects relatively young women, who often have few traditional risk factors, and is the commonest cause of a myocardial infarction associated with pregnancy. In contrast, FMD often remains silent but when manifested can also cause major sequelae, including renal infarction, stroke, cervical artery dissection and gut infarction. Here we provide an update on the diagnosis, aetiology and management of these important disorders that overwhelmingly affect women.

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants. METHODS: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses. RESULTS: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function. CONCLUSIONS: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

Generation of VCCRIi001-A, a human induced pluripotent stem cell line, from a patient with spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44-55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus, indicate a genetic predisposition to its pathophysiology. A human induced pluripotent stem cell line (hiPSC) was generated from a patient who had survived an episode of SCAD. This disease-specific hiPSC line will be useful for the study of SCAD after differentiation into blood vessel-forming cells.

Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus.

AIMS: Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridia patients. METHODS: We assessed a two-generation family: three individuals with aniridia, two previously diagnosed as type 2 diabetes. One individual with aniridia, with unknown diabetes status, was evaluated by oral glucose tolerance test. Genetic analysis of aniridia-associated genes was performed on all available family members. Candidate genes were functionally tested by gene silencing in MIN6 pancreatic ß-cells. RESULTS: A 25 year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484-630 kb deletion ∼120 kb distal to PAIRED BOX 6 (PAX6) showed dominant cosegregation with aniridia and diabetes in all affected family members. The deleted region contains regulatory elements for PAX6 expression and four additional coding regions. Knockdown of two of the deleted genes (Dnajc24 or Immp1l) with Pax6 impaired glucose-stimulated insulin secretion. CONCLUSIONS: We demonstrate dominant cosegregation of diabetes and aniridia with a deletion distal to PAX6, which is clinically distinct from the mild glucose intolerance previously reported with PAX6 coding mutations. Asymptomatic aniridia individuals appear at risk of diabetes (and its complications) and could benefit from earlier diagnosis and treatment.

Circulating n-3 fatty acids and trans-fatty acids, PLA2G2A gene variation and sudden cardiac arrest.

Whether genetic factors influence the associations of fatty acids with the risk of sudden cardiac arrest (SCA) is largely unknown. To investigate possible gene-fatty acid interactions on SCA risk, we used a case-only approach and measured fatty acids in erythrocyte samples from 1869 SCA cases in a population-based repository with genetic data. We selected 191 SNP in ENCODE-identified regulatory regions of fifty-five candidate genes in fatty acid metabolic pathways. Using linear regression and additive genetic models, we investigated the association of the selected SNP with erythrocyte levels of fatty acids, including DHA, EPA and trans-fatty acids among the SCA cases. The assumption of no association in non-cases was supported by analysis of publicly available datasets containing over 8000 samples. None of the SNP-fatty acid associations tested among the cases reached statistical significance after correction for multiple comparisons. One SNP, rs4654990 near PLA2G2A, with an allele frequency of 0·33, was nominally associated with lower levels of DHA and EPA and higher levels of trans-fatty acids. The strongest association was with DHA levels (exponentiated coefficient for one unit (1 % of total fatty acids), 0·90, 95 % CI 0·85, 0·97; P = 0·003), indicating that for subjects with a coded allele, the OR of SCA associated with one unit higher DHA is about 90 % what it is for subjects with one fewer coded allele. These findings suggest that the associations of circulating n-3 and trans-fatty acids with SCA risk may be more pronounced in carriers of the rs4654990 G allele.

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

BACKGROUND: Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest. METHODS: The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing. RESULTS: Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]). CONCLUSIONS: Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.

Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to intermarriage. The parent-child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.

Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.

A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans. BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored. METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS). RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (ß = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29). CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

Maternal genetic variation accounts in part for the associations of maternal size during pregnancy with offspring cardiometabolic risk in adulthood.

BACKGROUND: Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown. METHODS/RESULTS: In 1249 mother-offspring pairs recruited from the Jerusalem Perinatal Study, we used archival data to characterize ppBMI and GWG and follow-up data from offspring to assess CMR, including body mass index (BMI), waist circumference, glucose, insulin, blood pressure, and lipid levels, at an average age of 32. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk. We fit linear regression models to examine the associations of ppBMI and GWG with CMR traits with and without adjustment for GRS. Compared to unadjusted models, the coefficient for the association of a one-standard-deviation (SD) difference in GWG and offspring BMI decreased by 41% (95%CI -81%, -11%) from 0.847 to 0.503 and the coefficient for a 1SD difference in GWG and WC decreased by 63% (95%CI -318%, -11%) from 1.196 to 0.443. For other traits, there were no statistically significant changes in the coefficients for GWG with adjustment for GRS. None of the associations of ppBMI with CMR traits were significantly altered by adjustment for GRS. CONCLUSIONS: Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults.

Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA). OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk. METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases. RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase. CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.