Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Adiposity, Change in Adiposity, and Cognitive Decline in Mid- and Late Life.

OBJECTIVES: To examine associations between adiposity and adiposity change (loss, stable, gain) and subsequent longitudinal cognitive performance in African Americans in mid and late life. DESIGN: Cohort study using linear mixed models. SETTING: Genetic Epidemiology Network of Arteriopathy. PARTICIPANTS: African-American sibships with hypertension in Jackson, Mississippi (N = 1,108). MEASUREMENTS: Waist circumference and body mass index (BMI) were measured at two examinations 5 years apart. Stable adiposity was defined as values within 5% of the first measure. A composite cognitive Z-score was derived from individual cognitive test Z-scores at two study visits 6 years apart. RESULTS: Larger waist circumference was associated with greater rate of cognitive decline during follow-up (beta = -0.0009 per year, P = .001); BMI, change in waist circumference, and change in BMI were not associated with rate of decline. Loss of adiposity in midlife was associated with higher cognitive Z-scores in middle-aged individuals, and loss of adiposity in late life was associated with lower Z-scores in older adults (P = .01 for interaction between waist circumference and age; P = .04 for interaction between BMI and age). Simultaneous inclusion of waist circumference and BMI in the cross-sectional model suggested an association between larger waist circumference and poorer cognitive performance (beta = -0.009, P = .006) and between higher BMI and better cognitive performance (beta = 0.014, P = .06). CONCLUSION: The results suggested a differential pattern of the relationship between adiposity and cognition according to age (mid- or late life) and regional distribution of adiposity.

Associations Between Serum Inflammatory Markers and Hippocampal Volume in a Community Sample.

OBJECTIVES: To quantify associations between inflammatory biomarkers and hippocampal volume (HV) and to examine effect modification according to sex, race, and age. DESIGN: Cross-sectional analyses using generalized estimating equations to account for familial clustering; standardized ß-coefficients adjusted for age, sex, race, and education. SETTING: Community cohorts in Jackson, Mississippi and Rochester, Minnesota. PARTICIPANTS: The Genetic Epidemiology Network of Arteriopathy study. MEASUREMENTS: C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors 1 (sTNFR-1) and 2 (sTNFR-2) from peripheral blood were measured in a sample of 773 non-Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV. RESULTS: In the full sample, higher sTNFR-1 and sTNFR-2 were associated with smaller HV. Each standard deviation (SD) increase in sTNFR-1 was associated with 59.1 mm(3) (95% confidence interval (CI) = -101.4 to -16.7 mm(3) ) smaller HV and each SD increase in sTNFR-2 associated with 48.8 mm(3) (95% CI = -92.2 to -5.3 mm(3) ) smaller HV. Relationships were stronger for sTNFR-2 in men (HV = -116.6 mm(3) for each SD increase, 95% CI = -201.0 to -32.1) than women (HV = -26.0 per SD increase, 95% CI = -72.4-20.5) and sTNFR-1 in non-Hispanic whites (HV = -84.7 mm(3) per SD increase, 95% CI = -142.2 to -27.1) than African Americans (HV = -14.1 mm(3) per SD increase, 95% CI = -78.3-50.1). Associations between IL-6 or CRP and HV were not supported. CONCLUSION: Higher levels of sTNFRs were associated cross-sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late-life cognitive impairment.

Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: The term metabolic syndrome describes the clustering of risk factors found in many individuals with obesity. Because of their pathophysiology, we hypothesized that 2 features of metabolic syndrome, central obesity and insulin resistance (IR), would be associated with cerebrovascular changes on magnetic resonance imaging, and specifically with incident lacunar disease and not white matter hyperintensity (WMH) progression. METHODS: Risk factors were defined at study baseline in 934 participants in the Atherosclerosis Risk in Communities (ARIC) study, who completed 2 brain magnetic resonance imagings≈10 years apart. WMH progression and incident lacunes between the 2 magnetic resonance imagings were determined. An IR score for each participant was created using principal component analysis of 11 risk factors, including (among others): insulin, homeostatic model assessment-IR, body mass index, and waist circumference. Metabolic syndrome (presence/absence), using standard clinical definitions, and IR score at the first magnetic resonance imaging, were independent variables, evaluated in multivariate logistic regression to determine odds of WMH progression (Q5 versus Q1-Q4) and incident lacunes. RESULTS: Metabolic syndrome (adjusted odds ratio, 1.98; 95% confidence interval, 1.28-3.05) and IR score (adjusted odds ratio per 1-SD increase, 1.33; 95% confidence interval, 1.05-1.68) were associated with incident lacunes but not with WMH progression. Insulin, homeostatic model assessment-IR, and body mass index were not associated with incident lacunes or WMH progression in separate models. CONCLUSIONS: The IR score and central obesity are associated with incident lacunar disease but not WMH progression in individuals. Central obesity and IR may be important risk factors to target to prevent lacunar disease.

The metabolic syndrome and cognitive decline in the Atherosclerosis Risk in Communities study (ARIC).

BACKGROUND: Midlife metabolic syndrome (MetS) may impact cognitive health as a construct independently of hypertension, hyperlipidemia and other components. METHODS: 10,866 participants aged 45-64 years at baseline were assessed for MetS and completed cognitive testing at two later time points (3 and 9 years from the baseline visit). RESULTS: MetS is associated with increased odds of low cognitive performance in the domains of executive function and word fluency, but not with 6-year cognitive decline. Individual MetS components explained this association (hypertension, diabetes, low HDL, elevated triglycerides and increased waist circumference). CONCLUSIONS: A focus on the individual risk factors as opposed to MetS during midlife is important to reduce the incidence of cognitive impairment in later life.

Meta-analysis of loci associated with age at natural menopause in African-American women.

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

Physical activity and cardiovascular disease in African Americans in Atherosclerosis Risk in Communities.

PURPOSE: Although there is substantial evidence that physical activity reduces a person's risk of cardiovascular disease (CVD), few of these studies have included African Americans. The studies that have included African Americans offer inconclusive evidence on the association, and none studied heart failure separately. We used data from the Atherosclerosis Risk in Communities study cohort to examine, in African Americans, the association of physical activity with the incidence of CVD and its major components-stroke, heart failure, and CHD. METHODS: Participants age 45-64 yr (3707 African Americans and, for comparison, 10,018 Caucasians) had physical activity assessed via questionnaire in 1987 and were followed for incident CVD (n = 1039) through 2008. RESULTS: After adjustment for potential confounders, physical activity was inversely related to CVD, heart failure, and CHD incidence in both races (P values for trend <0.0001), and with stroke in African Americans. Hazard ratios (95% confidence intervals) for CVD for each higher physical activity category were similar by race: 1.0, 0.65 (0.56-0.75), and 0.59 (0.49-0.71) for African Americans and 1.0, 0.74 (0.66-0.83), and 0.67 (0.59-0.75) for Caucasians (P value for interaction = 0.38). CONCLUSIONS: Our findings reinforce recommendations that regular physical activity is important for CVD risk reduction in African Americans as well as Caucasians and support the idea that some physical activity is better than none.

Covert neurological symptoms associated with silent infarcts from midlife to older age: the Atherosclerosis Risk in Communities study.

BACKGROUND AND PURPOSE: Unrecognized or unreported stroke-like symptoms, called covert symptoms, occur in persons free of clinical stroke. Whether covert symptoms are associated with subclinical brain infarcts (SBIs) is unknown. This study examined the association between covert stroke-like symptoms and SBI/stroke in persons with no history of stroke or transient ischemic attack. METHODS: A total of 1881 Atherosclerosis Risk in Communities (ARIC) participants free of clinical stroke or transient ischemic attack (40% male, 50% black, 47-70 years) were queried for covert symptoms and underwent cerebral MRI during the baseline MRI visit. Symptoms were reassessed after 3 years at Visit 4 (n=1001; 39% male, 50% black) and approximately 10 years with a follow-up MRI (n=1006; 40% male, 50% black, 61-83 years). RESULTS: Covert symptoms were associated with prevalent SBI (OR, 1.94; 95% CI, 1.21-3.11; P=0.006). No support was found for associations between baseline MRI symptoms and SBI at the follow up MRI visit. In participants without SBI at baseline, symptoms at Visit 4 (OR, 2.96; 1.23-7.13; P=0.016) and symptoms at the follow-up MRI visit (OR, 4.29; 2.51-7.33; P<0.001) were associated with a combined outcome of new SBI/clinical stroke on follow-up MRI. Covert symptoms at follow-up MRI visit were also associated with having new SBI (OR, 2.26; 1.18-4.32; P=0.014) on the follow-up MRI that were not seen on the baseline MRI. CONCLUSIONS: Covert neurological symptoms were associated with prevalent SBI, and when ascertained at the time of follow-up MRI, with new SBI. Covert symptoms may reflect heightened risk for infarcts.

Breathing variability at rest is positively associated with 24-h blood pressure level.

BACKGROUND: Previous research has reported that inhibition of breathing can be observed in hypertensive patients at rest during the daytime, as well as in sleep at night. The present study hypothesized that the variability of breathing and end-tidal CO(2) (PetCO(2)) in seated women at rest is positively associated with their 24-h blood pressure level. METHODS: Breath-to-breath measures of breathing rate and tidal volume were recorded via inductive plethysmography in each of 54 women during two 20-min sessions of seated rest, and in 32 women during night time sleep. PetCO(2) was also recorded during these sessions via a respiratory gas monitor. Ambulatory blood pressure was recorded for 24 h between the two clinic sessions via oscillometry. RESULTS: Breath pauses >10 s were observed significantly more often in women in the upper than the lower tertile of 24-h systolic blood pressure. Breath-to-breath variability in breathing rate, tidal volume, and minute ventilation were greater in the higher blood pressure tertile women. Variability in PetCO(2) was also greater in high blood pressure tertile. These associations were independent of age, weight, and body surface area (BSA). Breathing variability was inversely correlated with heart rate variability (HRV). CONCLUSION: Greater variability in breathing at rest that is independent of metabolic activity characterizes women with elevated blood pressure. The linear association of breathing variability with 24-h blood pressure level is consistent with the hypothesis that intermittent breathing inhibition may predispose to the development of some forms of hypertension.