Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.Funding for collection, genotyping, and analysis of stroke samples was provided by Wellcome Trust Case Control Consortium-2, a functional genomics grant from the Wellcome Trust (DNA-Lacunar), the Stroke Association (DNA-lacunar), the Intramural Research Program of National Institute of Ageing (Massachusetts General Hospital [MGH] and Ischemic Stroke Genetics Study [ISGS]), National Institute of Neurological Disorders and Stroke (Siblings With Ischemic Stroke Study, ISGS, and MGH), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (MGH), Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (MGH), National Health and Medical Research Council (Australian Stroke Genetics Collaborative), and Italian Ministry of Health (Milan). Additional support for sample collection came from the Medical Research Council, National Institute of Health Research Biomedical Research Centre and Acute Vascular Imaging Centre (Oxford), Wellcome Trust and Binks Trust (Edinburgh), and Vascular Dementia Research Foundation (Munich). MT is supported by a project grant from the Stroke Association (TSA 2013/01). HSM is supported by an NIHR Senior Investigator award. HSM and SB are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. VT and RL are supported by grants from FWO Flanders. PR holds NIHR and Wellcome Trust Senior Investigator Awards. PAS is supported by an MRC Fellowship. CML’s research is supported by the National Institute for Health Research Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and the BRC for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

Visceral Adiposity and Insular networks: Associations with Food Craving

Background/objectives: Accumulation of visceral adiposity can disrupt the brain’s sensitivity to interoceptive feedback, which is coded in the insula. This study aimed to test the link between visceral fat and the functional connectivity of two insulae regions relevant for eating behavior: the middle-dorsal insula (mIns), which codes homeostatic changes, and the rostral insula (rIns), which codes stable representations of food properties. We also assessed the impact of visceral adiposity-associated insulae networks on food craving. Subjects/methods: Seventy-five adults ranging in weight status (normal and excess weight) underwent resting-state functional magnetic resonance imaging (fMRI) and subjective food craving measures. We examined the association between visceral fat and seed-based functional connectivity of the mIns and the rIns, controlling for BMI, age, and sex, using multiple regressions in SPM8. We also tested if visceral fat mediated the association between insulae connectivity and food craving. Results: Higher visceral adiposity was associated with decreased connectivity between the mIns and a cluster involving the hypothalamus and the bed nucleus of the stria terminalis. Decreased connectivity in this network was associated with greater food craving, a relation mediated by visceral adiposity. Visceral adiposity was also associated with increased connectivity between the mIns and the middle frontal gyri and the right intraparietal cortex, and between the rIns and the right amygdala. Conclusions: Accumulation of visceral adiposity is linked to disrupted functional connectivity within the mIns and rIns networks. Furthermore, the link between the mIns network and food craving is mediated by visceral fat. Findings suggest that visceral fat disrupts insula coding of bodily homeostatic signals, which may boost externally driven food cravings