Mid-Life Physical Activity and Late-Life Cognitive Performance among American Indians.

INTRODUCTION: Research on factors associated with late-life cognitive performance in diverse racial/ethnic groups is increasingly important due to the growing size and racial diversity of the elder population. METHODS: Using data on American Indians (AIs) from the Strong Heart Study, we measured associations between mid-life physical activity (PA), assessed by a questionnaire or pedometer, and performance on tests of general cognitive function, phonemic fluency, verbal learning and memory, and processing speed. Cognitive tests were administered 7-21 years after PA measurements. To estimate associations, we used regression models with and without inverse-probability weights to account for potential attrition bias in the cohort. RESULTS: Questionnaire and pedometer measures of PA were positively associated with cognitive function. Participants in the top quartile of questionnaire-based PA had Modified Mini-Mental State examination scores 3.2 (95% CI: 1.5-4.9) points higher than participants in the lowest quartile. Phonemic fluency scores also trended higher for participants in the top compared to the bottom categories for both PA measures: top questionnaire quartile = 2.7 (95% CI: 0.6-4.8) points higher and top pedometry tertile = 6.7 (95% CI: 2.7-10.7) points higher. We observed no associations between PA and tests assessing verbal learning and memory, or processing speed. Weighted model results were similar, but less precise. CONCLUSIONS: In this cohort of AIs with relatively low levels of PA, positive associations between mid-life PA and late-life cognitive performance were dose-dependent and of modest clinical significance.

Substance use and mental health in pregnant women during the COVID-19 pandemic.

OBJECTIVES: We examined the prevalence of substance use as a coping mechanism and identified relationships between maternal mental health over time and use of substances to cope during the Coronavirus Disease 2019 (COVID-19) pandemic among pregnant women in the U.S.A. METHODS: Self-reported repeated measures from 83 pregnant women were collected online in April 2020 and May 2020. Women retrospectively reported their mental/emotional health before the pandemic, as well as depression, stress, and substance use as a result of the pandemic at both time points. Linear regression measured cross-sectional and longitudinal associations between mental health and substance use. RESULTS: Pre-COVID-19 reports of poorer mental/emotional health (b = 0.46) were significantly (p < .05) associated with number of substances used to cope with the pandemic. Elevated stress (b = 0.35) and depressive symptoms (b = 0.27) and poorer mental/emotional health (b = 0.14) in April were also significantly related to higher numbers of substances used in May (p < .05). CONCLUSION: Pregnant women's psychological well-being may be a readily measured indicator substance use risk during crises such as the COVID-19 pandemic. Interventions addressing increased stress and depression may also mitigate the emergence of greater substance use among pregnant women.

Stressors, coping, and resources needed during the COVID-19 pandemic in a sample of perinatal women.

BACKGROUND: Psychological stress and coping experienced during pregnancy can have important effects on maternal and infant health, which can also vary by race, ethnicity, and socioeconomic status. Therefore, we assessed stressors, coping behaviors, and resources needed in relation to the COVID-19 pandemic in a sample of 162 perinatal (125 pregnant and 37 postpartum) women in the United States. METHODS: A mixed-methods study captured quantitative responses regarding stressors and coping, along with qualitative responses to open-ended questions regarding stress and resources needed during the COVID-19 pandemic. Logistic and linear regression models were used to analyze differences between pregnant and postpartum participants, as well as differences across key demographic variables. Qualitative content analysis was used to analyze open-ended questions. RESULTS: During the COVID-pandemic, food scarcity and shelter-in-place restrictions made it difficult for pregnant women to find healthy foods. Participants also reported missing prenatal appointments, though many reported using telemedicine to obtain these services. Financial issues were prevalent in our sample and participants had difficulty obtaining childcare. After controlling for demographic variables, pregnant women were less likely to engage in healthy stress-coping behaviors than postpartum women. Lastly, we were able to detect signals of increased stressors induced by the COVID-19 pandemic, and less social support, in perinatal women of racial and ethnic minority, and lower-income status. Qualitative results support our survey findings as participants expressed concerns about their baby contracting COVID-19 while in the hospital, significant others missing the delivery or key obstetric appointments, and wanting support from friends, family, and birthing classes. Financial resources, COVID-19 information and research as it relates to maternal-infant health outcomes, access to safe healthcare, and access to baby supplies (formula, diapers, etc.) emerged as the primary resources needed by participants. CONCLUSIONS: To better support perinatal women's mental health during the COVID-19 pandemic, healthcare providers should engage in conversations regarding access to resources needed to care for newborns, refer patients to counseling services (which can be delivered online/via telephone) and virtual support groups, and consistently screen pregnant women for stressors.

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

Parental Depression Symptoms at Neonatal Intensive Care Unit Discharge and Associated Risk Factors.

OBJECTIVE: To investigate the prevalence and risk factors associated with parental depressive symptoms at neonatal intensive care unit (NICU) discharge and determine the relationships among depressive symptoms, stress, and social support. STUDY DESIGN: Parents participating in the Giving Parents Support trial (n = 300) were surveyed before NICU discharge. Depressive symptoms, stress, and social support were assessed using the Center for Epidemiological Studies Depression Scale (CESD-10), Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU), Perceived Stress Scale (PSS-10), and Multidimensional Scale of Perceived Social Support (MSPSS). Regression analyses examined relationships among depressive symptoms, stress, social support, and parent/infant factors. RESULTS: At NICU discharge, 45% of parents reported depressive symptoms and 43% reported elevated perceived stress. Increased odds of elevated depressive symptoms were associated with older gestational age (P = .02), female infant (P = .02), and longer length of stay (P = .045). Odds of depression were 7.87 (95% CI, 2.15-28.75) for parents of infants with gestational age ≥37 weeks compared with gestational age <28 weeks. Parental NICU stress was higher in younger parents (P < .01). Depressive symptoms were positively associated with parental stress. Each 1-point increase in PSS:NICU score was associated with a 2.1-point (95% CI, 1.6-2.9; P < .001) increase in CESD-10 score. Social support was inversely associated with depressive symptoms. CONCLUSION: The prevalence of depressive symptoms in parents at NICU discharge was high, even among parents of term infants. Older gestational age, greater parental stress, and lower levels of social support were strong correlates of depressive symptoms. Strategies to support parents, including depression screening, stress reduction strategies, and mental health referrals, are needed.

A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted ß = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted ß = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.

Vascular Risk Factors and Findings on Brain MRI of Elderly Adult American Indians: The Strong Heart Study.

BACKGROUND: Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians. METHODS: Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes. RESULTS: -Hypertension was associated with the presence of infarcts (p = 0.001), ventricle enlargement (p = 0.01), and increased white matter hyperintensity volume (p = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (p < 0.001), ventricular enlargement (p = 0.001), and sulcal widening (p = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes. CONCLUSIONS: This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.

Lifestyle Risk Factors and Findings on Brain Magnetic Resonance Imaging of Older Adult American Indians: The Strong Heart Study.

BACKGROUND: Clinical stroke is prevalent in American Indians, but the lifestyle risk factors for vascular brain injury have not been well-studied in this population. The purpose of this study was to correlate brain magnetic resonance imaging (MRI) findings with obesity, alcohol use, and smoking behaviors in elderly American Indians from the Strong Heart Study. METHODS: Cranial MRI scans (n = 789) were analyzed for dichotomous measures of infarcts, hemorrhages, white matter hyperintensities (WMH), and cerebral atrophy and continuous measures of total brain, WMH, and hippocampal volume. Poisson regression was used to estimate prevalence ratios, and linear regression was used to estimate measures of association for continuous outcomes. Models were adjusted for the risk factors of interest as well as age, sex, study site, income, education, hypertension, diabetes, and low-density lipoprotein cholesterol. RESULTS: Smoking was associated with increased hippocampal atrophy (p = 0.002) and increased prevalence of sulcal widening (p < 0.001). Relative to nonsmokers, smokers with more than 25 pack-years of smoking had a 27% (95% CI 7-47%) increased prevalence of high-grade sulci, p = 0.005. Body mass index was inversely associated with prevalence of nonlacunar infarcts and sulcal widening (all p = 0.004). Alcohol use was not significantly associated with any of the measured MRI findings. CONCLUSIONS: This study found similar associations between smoking and vascular brain injury among American Indians, as seen in other populations. In particular, these findings support the role of smoking as a key correlate for cerebral atrophy.

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women.

Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012-2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women.

Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans.

Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor allele frequency, MAF ≥5%) or infrequent (0.5% < MAF < 5%) variants across the exome in African Americans. Using a reference panel of 1692 African Americans and 471 Europeans from the National Heart, Lung, and Blood Institute's (NHLBI) Exome Sequencing Project (ESP), we imputed whole-exome sequence data into 13 719 African Americans with existing array-based GWAS data (discovery). Variants achieving a height-association threshold of P < 5E-06 in the imputed dataset were followed up in an independent sample of 1989 African Americans with whole-exome sequence data (replication). We used P < 2.5E-07 (=0.05/196 779 variants) to define statistically significant associations in meta-analyses combining the discovery and replication sets (N = 15 708). We discovered and replicated three independent loci for association: 5p13.3/C5orf22/rs17410035 (MAF = 0.10, ß = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, ß = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; ß = 0.47 cm; P = 4.7E-09). Conditional analyses suggested 5p13.3 (C5orf22/rs17410035) and 13q14.2 (SPRYD7/rs114089985) may harbor novel height alleles independent of previous GWAS-identified variants (r(2) with GWAS loci <0.01); whereas 17q23.3/GH2/rs2006123 was correlated with GWAS-identified variants in European and African populations. Notably, 13q14.2/rs114089985 is infrequent in African Americans (MAF = 3%), extremely rare in European Americans (MAF = 0.03%), and monomorphic in Asian populations, suggesting it may be an African-American-specific height allele. Our findings demonstrate that whole-exome imputation of sequence variants can identify low-frequency variants and discover novel variants in non-European populations.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women.

OBJECTIVE: Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm. APPROACH AND RESULTS: Using a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm. CONCLUSIONS: As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women.

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

Fine-mapping and initial characterization of QT interval loci in African Americans.

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.

OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

Genome-wide association study of body height in African Americans: the Women's Health Initiative SNP Health Association Resource (SHARe).

Height is a complex trait under strong genetic influence. To date, numerous genetic loci have been associated with height in individuals of European ancestry. However, few large-scale discovery genome-wide association studies (GWAS) of height in minority populations have been conducted and thus information about population-specific height regulation is limited. We conducted a GWA analysis of height in 8149 African-American (AA) women from the Women's Health Initiative. Genetic variants with P< 5 × 10(-5) (n = 169) were followed up in a replication data set (n = 20 809) and meta-analyzed in a total of 28 958 AAs and African-descent individuals. Twelve single-nucleotide polymorphisms (SNPs) representing 7 independent loci were significantly associated with height at P < 5 × 10(-8). We identified novel SNPs in 17q23 (TMEM100/PCTP) and Xp22.3 (ARSE) reflecting population-specific regulation of height in AAs and replicated five loci previously reported in European-descent populations [4p15/LCORL, 11q13/SERPINH1, 12q14/HMGA2, 17q23/MAP3K3 (mitogen-activated protein kinase3) and 18q21/DYM]. In addition, we performed an admixture mapping analysis of height which is both complementary and supportive to the GWA analysis and suggests potential associations between ancestry and height on chromosomes 4 (4q21), 15 (15q26) and 17 (17q23). Our findings provide insight into the genetic architecture of height and support the investigation of non-European-descent populations for identifying genetic factors associated with complex traits. Specifically, we identify new loci that may reflect population-specific regulation of height and report several known height loci that are important in determining height in African-descent populations.