The Purdue Pegboard Test: Normative Data From 1,355 Healthy People From Austria.

IMPORTANCE: The Purdue Pegboard Test (PPT) is widely used as a measure of manual dexterity. Declining manual dexterity may predict cognitive decline among elderly people, but normative data for this population are scarce. OBJECTIVE: To identify demographic and clinical predictors of PPT results in normal middle-aged and elderly Austrian people and to provide norms stratified by significant determinants. DESIGN: A prospective, community-based cohort study using baseline data of participants from two study panels (1991-1994 and 1999-2003). SETTING: Monocentric study Participants: 1,355 healthy, randomly selected, community-dwelling people ages 40 to 79 yr. METHOD: Extensive clinical examination, including completion of the PPT. OUTCOMES AND MEASURES: The number of pegs placed within a 30-s time limit on four subtests: using the right hand, left hand, both hands, and assembly (within 60 s), respectively. Demographic outcomes were the highest grade achieved. RESULTS: For all four subtests, increasing age (ßs = -0.400 to -0.118, SEs = 0.006 to 0.019, p < .001) and male sex (ßs = -1.440 to -0.807, SEs = 0.107 to 0.325, p < .001) was related to worse test results. Among vascular risk factors, diabetes (ßs = -1.577 to -0.419, SEs = 0.165 to 0.503, p < .001) was related to worse test results but explained only a small portion (0.7%-1.1%) of the variability in PPT performance. CONCLUSIONS AND RELEVANCE: We provide age- and sex-specific norms of the PPT for a middle-aged and elderly population. The data represent useful reference values when assessing manual dexterity in older age groups. What This Article Adds: Advancing age and male sex relate to worse performance on the PPT in a community-dwelling cohort without signs and symptoms of neurological disease. Vascular risk factors explain only very little of the variance of test results in our population. Our study adds to the limited age- and sex-specific norms of the PPT among middle-aged and older people.

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Vitamin D and cognitive function: A Mendelian randomisation study.

The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.

Interventions to reduce the stigma of eating disorders: A systematic review and meta-analysis.

Stigma is a problem for individuals with eating disorders (EDs), forming a barrier to disclosure and help-seeking. Interventions to reduce ED stigma may help remove these barriers; however, it is not known which strategies (e.g., explaining etiology to reduce blame, contact with a person with an ED, or educating about ED) are effective in reducing stigma and related outcomes. This review described effectiveness of intervention strategies, and identified gaps in the literature. A search of four databases was performed using the terms (eating disorder* OR bulimi* OR anorexi* OR binge-eating disorder) AND (stigma* OR stereotyp* OR beliefs OR negative attitudes) AND (program OR experiment OR intervention OR education), with additional texts sought through LISTSERVs. Two raters screened papers, extracted data, and assessed quality. Stigma reduction strategies and study characteristics were examined in critical narrative synthesis. Exploratory meta-analysis compared the effects of biological and sociocultural explanations of EDs on attitudinal stigma. Eighteen papers were eligible for narrative synthesis, with four also eligible for inclusion in a meta-analysis. Biological explanations reduced stigma relative to other explanations, including sociocultural explanations in meta-analysis (g = .47, p < .001). Combined education and contact interventions improved stigma relative to control groups or over time. Most studies examined Anorexia Nervosa (AN) stigma and had mostly female, undergraduate participants. Despite apparent effectiveness, research should verify that biological explanations do not cause unintentional harm. Future research should evaluate in vivo contact, directly compare education and contact strategies, and aim to generalize findings across community populations.

No evidence for increased brain iron deposition in patients with ischemic white matter disease.

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging-based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease.

Fitness and cognition in the elderly: The Austrian Stroke Prevention Study.

OBJECTIVE: To investigate whether greater cardiorespiratory fitness is associated with better global and domain-specific cognitive function. METHODS: We investigated 877 participants (aged 65 ± 7 years, 55% women) of the Austrian Stroke Prevention Study. For cardiorespiratory fitness, the maximum oxygen consumption (V̇o2max) was calculated based on weight and maximum and resting heart rate on a treadmill test (mL·kg(-1)·min(-1)). A test battery assessing memory (Bäumler's Lern-und Gedächtnistest), executive function (Wisconsin Card Sorting Test, Trail Making Test-Part B, Digit Span Backward, Alters Konzentrationstest, a computerized complex reaction time task) and motor skills (Purdue Pegboard Test) was administered. Summary measures for cognitive domains and for global cognition were calculated. White matter lesions, lacunes, and brain atrophy were assessed using MRI. RESULTS: Higher V̇o2max was associated with better global (B = 0.024; p = 0.000) and domain-specific cognitive function (memory B = 0.026, p = 0.000; executive function B = 0.009, p = 0.003; motor skills B = 0.012, p = 0.018) after adjustment for age, sex, education years, and Ca(2+) channel antagonists or ß-blockers. White matter lesions, lacunes, or brain atrophy did not mediate the effect (p > 0.05 for all mediators). The interactions of V̇o2max with age, overweight, and APOE ε4 on cognition were not statistically significant (p > 0.05 for all interaction terms) with the exception of a modulating effect of body mass index on V̇o2max in the memory domain. CONCLUSIONS: Higher V̇o2max is associated with better global cognitive function and with better performance in the cognitive domains of memory, executive function, and motor skills in the middle-aged and elderly. The association is not mediated by the presence of white matter lesions, lacunes, and brain atrophy.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

R2* mapping for brain iron: associations with cognition in normal aging.

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.

Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults.

In the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility--a surrogate marker of brain iron--of these gray matter structures with behavioral measures of motor and cognitive abilities, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes.

HPV vaccination in women aged 27 to 45 years: what do general practitioners think?

BACKGROUND: Although the Human Papillomavirus (HPV) vaccine is registered in Australia for females aged 9 to 45 years, females aged 27 to 45 years have shown limited vaccine uptake. Our study explored general practitioners' (GPs) views concerning HPV vaccination of females in this age group, with particular focus on the barriers and the facilitators to the delivery of the HPV vaccine. METHODS: Semi-structured telephone interviews were conducted with 24 randomly selected general practitioners from metropolitan Melbourne. Questions were based on a theoretical framework that explained the barriers and facilitators to professional behaviour change. RESULTS: According to the GPs, the major barriers to the uptake of the HPV vaccine included the cost of the vaccine, time constraints, and the three-dose schedule. Other barriers that were identified included GPs' and patients' beliefs that females in this age group were at low risk of contracting HPV, lack of awareness about the vaccine, and uncertainty about the benefits of this vaccine for females in this age group. In contrast, the facilitators that were identified included the availability of the vaccine on site, the availability of vaccine clinics or nurses for administering the vaccine, the availability of information related to the vaccine either on site or online, and positive opinions from experts in the field. CONCLUSIONS: Our study has identified some of the barriers and facilitators to the delivery and uptake of the HPV vaccine in females aged 27 to 45 years, as perceived by GPs. Further studies should be conducted to determine which of these should be targeted or prioritised for intervention. The views of women in this age group should also be considered as these would also be influential in designing effective intervention strategies for improving the delivery and uptake of the HPV vaccine.

Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study.

BACKGROUND: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology. METHODS: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability. RESULTS: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance. CONCLUSIONS: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.

The molecular genetic architecture of self-employment.

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σ(g)(2)/σ(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.

HPV vaccination of adult women: an audit of Australian general practitioners.

BACKGROUND: While initial Human Papillomavirus (HPV) vaccine uptake estimates are encouraging, especially in the school-aged population, it is unclear to what extent general practitioners (GPs) have been recommending and administering the vaccine to adult women and what the uptake has been. METHODS: A mixed methods study of Australian GPs consisting of a knowledge and attitudes questionnaire and an audit which assessed overall vaccination rates since commencement of the Australian National HPV program and in the last 50 female patients aged 27-45 years who consulted them. RESULTS: GPs have a good level of knowledge regarding HPV vaccination and are strongly committed to it for women until 27 years but are much less so for women aged 27-45 years. From 2007 to 2010, only 1.9% of women aged 27-45 who consulted the GPs commenced HPV vaccination. Of those, however, the majority completed all three doses. Higher rates of commencement of HPV vaccination (11.4%) were demonstrated by auditing the last 50 consecutive patients seen by the GP. In this group of women, 63% had received a Pap test in the last two years. Female GPs had significantly higher rates of vaccination. CONCLUSIONS: There is relatively low HPV vaccine uptake in women aged 27-45. Once HPV vaccination is commenced, however, completion rates are high in women in this age group. Low uptake may be due to lack of opportunistic awareness raising in relevant consultations. Clear guidance together with further exploration of patient factors and GP barriers and enablers would assist implementation of HPV vaccination.

White matter lesion progression in LADIS: frequency, clinical effects, and sample size calculations.

BACKGROUND AND PURPOSE: White matter lesion (WML) progression has been advocated as a surrogate marker in intervention trials on cerebral small vessel disease. We assessed the rate of visually rated WML progression, studied correlations between lesion progression and cognition, and estimated sample sizes for clinical trials with pure WML progression vs combined WML progression-cognitive outcomes. METHODS: Those 394 participants of the Leukoaraiosis and Disability Study (LADIS) study with magnetic resonance imaging scanning at baseline and 3-year follow-up were analyzed. WML progression rating relied on the modified Rotterdam Progression Scale. The Vascular Dementia Assessment Scale global score and a composite score of specific executive function tests assessed longitudinal change in cognition. Sample size calculations were based on the assumption that treatment reduces WML progression by 1 grade on the Rotterdam Progression Scale. RESULTS: WML progression related to deterioration in cognitive functioning. This relationship was less pronounced in subjects with early confluent and confluent lesions. Consequently, studies in which the outcome is cognitive change resulting from treatment effects on lesion progression will need between 1809 subjects per treatment arm when using executive tests and up to 18 853 subjects when using the Vascular Dementia Assessment Scale score. Studies having WML progression as the sole outcome will need only 58 or 70 individuals per treatment arm. CONCLUSIONS: WML progression is an interesting outcome for proof-of-concept studies in cerebral small vessel disease. If cognitive outcome measures are added to protocols, then sample size estimates increase substantially. Our data support the use of an executive test battery rather than the Vascular Dementia Assessment Scale as the primary cognitive outcome measure.

Vascular risk factors, white matter hyperintensities and hippocampal volume in normal elderly individuals.

BACKGROUND/AIMS: Hippocampal atrophy has been identified as marker for the development of Alzheimer's dementia (AD). To what extent vascular risk factors and white matter hyperintensities (WMH) affect hippocampal volume (HV) in asymptomatic elderly subjects and thus may impact such a predictive capacity is controversial. METHODS: We analysed 287 participants of the Austrian Stroke Prevention Study (mean age 66.6 ± 6.6 years) with a Mini Mental State Examination score ≥27 who were free of neuropsychiatric disease and had undergone MRI including coronal T(1)-weighted sequences allowing for semi-automatic assessment of HV. Global brain volume (BV) was measured using SIENAX. WMH were rated according to the Fazekas scale and segmented to obtain WMH volumes. RESULTS: Higher age was associated with lower absolute and normalized HV, a lower BV and higher WMH volume. None of the vascular risk factors had an impact on HV except for high-density lipoprotein. This effect disappeared after normalization of HV. WMH severity and volume did not affect HV either. CONCLUSION: Our data indicate HV loss in parallel with the whole brain and suggest no specific vulnerability towards vascular risk factors or age-related WMH in a cognitively intact normal elderly population. This also supports the utility of HV measurements to identify impending AD.

White matter hyperintensities alter functional organization of the motor system.

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.