Low-level lithium in drinking water and subsequent risk of dementia: Cohort study.

BACKGROUND: Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. AIMS: We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. METHOD: Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. RESULTS: The mean lithium level at all sampling sites was 1.45 µg/L (SD 1.83, range 0.5-18.2) and was 1.26 (SD 0.63, range 0.55-9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04-1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81-1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55-0.68 µg/L) in all deciles except the highest, corresponding with lithium levels 0.68-2.1 µg/L. CONCLUSIONS: Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 µg/L.

Polygenic predictors of age-related decline in cognitive ability.

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initial n = 1091 age 70; final n = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardized ß-values = -0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardized ß = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However, APOE e4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardized ß = -0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par with APOE e4, a better-established predictor.

Multidimensional Apathy in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia, and Alzheimer Disease.

Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD (P < .01) and significantly higher apathy over all subtypes than patients with PPA (Ps < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy (P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

Aluminium and fluoride in drinking water in relation to later dementia risk.

BACKGROUND: Environmental risk factors for dementia are poorly understood. Aluminium and fluorine in drinking water have been linked with dementia but uncertainties remain about this relationship. AIMS: In the largest longitudinal study in this context, we set out to explore the individual effect of aluminium and fluoride in drinking water on dementia risk and, as fluorine can increase absorption of aluminium, we also examine any synergistic influence on dementia. METHOD: We used Cox models to investigate the association between mean aluminium and fluoride levels in drinking water at their residential location (collected 2005-2012 by the Drinking Water Quality Regulator for Scotland) with dementia in members of the Scottish Mental Survey 1932 cohort who were alive in 2005. RESULTS: A total of 1972 out of 6990 individuals developed dementia by the linkage date in 2012. Dementia risk was raised with increasing mean aluminium levels in women (hazard ratio per s.d. increase 1.09, 95% CI 1.03-1.15, P < 0.001) and men (1.12, 95% CI 1.03-1.21, P = 0.004). A dose-response pattern of association was observed between mean fluoride levels and dementia in women (1.34, 95% CI 1.28-1.41, P < 0.001) and men (1.30, 95% CI 1.22-1.39, P < 0.001), with dementia risk more than doubled in the highest quartile compared with the lowest. There was no statistical interaction between aluminium and fluoride levels in relation with dementia. CONCLUSIONS: Higher levels of aluminium and fluoride were related to dementia risk in a population of men and women who consumed relatively low drinking-water levels of both.

DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921.

BACKGROUND: Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia. METHODS: Study subjects (n = 488) were members of the Lothian Birth Cohort 1921. Dementia case ascertainment used data from death certificates, electronic hospital records, and clinical reviews. Venous blood samples were taken at baseline, at age 79 years. DNA methylation and measures of epigenetic age were calculated in accordance with Horvath's epigenetic clock tutorial, using the online calculator (https://dnamage.genetics.ucla.edu/). From these values, four measures of accelerated ageing were calculated: extrinsic epigenetic age acceleration (EEAA), intrinsic epigenetic age acceleration (IEAA), AgeAccelPheno and AgeAccelGrim. Competing risk regression models - with death as a competing risk - were performed to examine the association between each measure of accelerated ageing and incident dementia. APOE ɛ4 status, sex, age, smoking status, history of cardiovascular disease, cerebrovascular disease, hypertension, and diabetes were included as covariates. RESULTS: None of the multivariate models revealed a positive association between increased epigenetic age acceleration and dementia risk. Across all included models, never-smoking increased risk for dementia (HR 1.69 [1.06, 2.71], p = 0.03), and having no APOE ɛ4 alleles reduced risk for dementia (HR 0.44 [0.29, 0.67], p < 0.001). CONCLUSIONS: The present study did not demonstrate any consistent association between DNA methylation-based measures of accelerated ageing and dementia in subjects aged over 79 years. Further, larger studies - including separate analyses of dementia subtypes - are required to further investigate the potential association between DNA methylation-based measures of accelerated ageing and dementia.

Fluctuating asymmetry in brain structure and general intelligence in 73-year-olds.

Fluctuating body asymmetry is theorized to indicate developmental instability, and to have small positive associations with low socioeconomic status (SES). Previous studies have reported small negative associations between fluctuating body asymmetry and cognitive functioning, but relationships between fluctuating brain asymmetry and cognitive functioning remain unclear. The present study investigated the association between general intelligence (a latent factor derived from a factor analysis on 13 cognitive tests) and the fluctuating asymmetry of four structural measures of brain hemispheric asymmetry: cortical surface area, cortical volume, cortical thickness, and white matter fractional anisotropy. The sample comprised members of the Lothian Birth Cohort 1936 (LBC1936, N = 636, mean age = 72.9 years). Two methods were used to calculate structural hemispheric asymmetry: in the first method, regions contributed equally to the overall asymmetry score; in the second method, regions contributed proportionally to their size. When regions contributed equally, cortical thickness asymmetry was negatively associated with general intelligence (ß = -0.18,p < .001). There was no association between cortical thickness asymmetry and childhood SES, suggesting that other mechanisms are involved in the thickness asymmetry-intelligence association. Across all cortical metrics, asymmetry of regions identified by the parieto-frontal integration theory (P-FIT) was not more strongly associated with general intelligence than non-P-FIT asymmetry. When regions contributed proportionally, there were no associations between general intelligence and any of the asymmetry measures. The implications of these findings, and of different methods of calculating structural hemispheric asymmetry, are discussed.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Epigenome-wide association study of lung function level and its change.

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

Meta-analysis of epigenome-wide association studies of cognitive abilities.

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders.

Epigenetics has classically been recognized as crucial to neurodevelopment and neurodevelopmental disorders. More recently its role in ageing processes, including neurodegenerative disorders has emerged, although far more research is required in this area, particularly in humans. Epigenetic processes that regulate gene expression comprise strata of DNA modification (e.g. methylation), histone modification (e.g. histone acetylation), and mRNA translation (e.g. by microRNAs). These strata are progressively more fluid whereby changes in DNA methylation may persist for many years whilst expression of microRNAs fluctuates over short periods. There is considerable 'cross-talk' between these epigenetic strata. Epigenetic mechanisms are open to parental imprinting and thus they are candidates for linking diseases, not just over the life course, but also intergenerationally. There is a genetic overlap between intellectual disability and cognitive ageing. Epigenetic pathways may strengthen the links between neurodevelopmental disorders and neurodegenerative diseases. WHAT THIS PAPER ADDS: DNA methylation has relevance to both neurological development and neurodegeneration. Links between epigenetics, genotype and phenotype are emerging.

ENVEJECIMIENTO Y EPIGENÉTICA: VINCULACIÓN EL NEURODESARROLLO Y TRASTORNOS NEURODEGENERATIVOS: La epigenética ha sido reconocida clásicamente como crucial para el neurodesarrollo y los trastornos del neurodesarrollo. Más recientemente, se ha propuesto, su papel en los procesos de envejecimiento, incluidos los trastornos neurodegenerativos, aunque se requiere mucha más investigación en esta área, particularmente en humanos. Los procesos epigenéticos que regulan la expresión génica comprenden estratos de modificación de ADN (por ejemplo, metilación), modificación de histonas (por ejemplo, acetilación de histonas) y traducción de ARNm (por ejemplo, por microARN). Estos estratos son cada vez más dinámicos, por lo que los cambios en la metilación del ADN pueden persistir durante muchos años, mientras que la expresión de los microARN fluctúa durante períodos cortos. Existe una considerable "conversación cruzada" entre estos estratos epigenéticos. Los mecanismos epigenéticos están abiertos a la impronta parental y, por lo tanto, son candidatos para vincular enfermedades, no solo en el transcurso de la vida, sino también intergeneracionalmente. Existe una superposición genética entre la discapacidad intelectual y el envejecimiento cognitivo. Las vías epigenéticas pueden fortalecer los vínculos entre los trastornos del neurodesarrollo y las enfermedades neurodegenerativas.

ENVELHECIMENTO E EPIGENÉTICA: LIGANDO TRANSTORNOS NEURODESENVOLVIMENTAIS E NEURODEGENERATIVAS: A epigenética tem sido classicamente reconhecida como crucial para o neurodesenvolvimento e transtornos neurodesenvolvimentais. Mais recentemente, seu papel nos processos de envelhecimento, incluindo doenças neurodegenerativas emergiu, embora muito mais pesquisas sejam necessárias nesta área, particularmente em humanos. Processos epigenéticos que regulam a expressão gênica incluem estratos de modificação de DNA (ex: metilação), modificação de histonas (ex: acetilação de histonas), e translação de mRNA (ex: por micro RNAs). Estes estratos são progressivamente mais fluidos, portanto mudanças na metilação do DNA podem persistir por muitos anoss, enquanto a expressão de micro RNAs flutua por curtos períodos. Há considerável troca entre estes estratos epigenéticos. Mecanismos epigenéticos são abertos ao impressão genómica (imprinting parental), e portanto, candidados a se relacionar com doenças, não apenas no curso da vida, mas também entre gerações. Há sobreposição genética entre deficiência intelectual e envelhecimento cognitivo. Vias epigenéticas podem fortalecer as relações entre transtornos neurodesenvolvimentais e doenças neurodegenerativas.

Predicting change in quality of life from age 79 to 90 in the Lothian Birth Cohort 1921.

PURPOSE: Quality of life (QoL) decreases in very old age, and is strongly related to health outcomes and mortality. Understanding the predictors of QoL and change in QoL amongst the oldest old may suggest potential targets for intervention. This study investigated change in QoL from age 79 to 90 years in a group of older adults in Scotland, and identified potential predictors of that change. METHOD: Participants were members of the Lothian Birth Cohort 1921 who attended clinic visits at age 79 (n = 554) and 90 (n = 129). Measures at both time points included QoL (WHOQOL-BREF: four domains and two single items), anxiety and depression, objective health, functional ability, self-rated health, loneliness, and personality. RESULTS: Mean QoL declined from age 79 to 90. Participants returning at 90 had scored significantly higher at 79 on most QoL measures, and exhibited better objective health and functional ability, and lower anxiety and depression than non-returners. Hierarchical multiple regression models accounted for 20.3-56.3% of the variance in QoL at age 90. Baseline QoL was the strongest predictor of domain scores (20.3-35.6% variance explained), suggesting that individual differences in QoL judgements remain largely stable. Additional predictors varied by the QoL domain and included self-rated health, loneliness, and functional and mood decline between age 79 and 90 years. CONCLUSIONS: This study has identified potential targets for interventions to improve QoL in the oldest old. Further research should address causal pathways between QoL and functional and mood decline, perceived health and loneliness.

KLB is associated with alcohol drinking, and its gene product ß-Klotho is necessary for FGF21 regulation of alcohol preference.

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified ß-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). ß-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific ß-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

Predicting incident dementia 3-8 years after brief cognitive tests in the UK Biobank prospective study of 500,000 people.

INTRODUCTION: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. METHODS: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. RESULTS: We found associations of cognitive task performance with all-cause and cause-specific dementia (P <  .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. DISCUSSION: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

Cognitive function in early and later life is associated with blood glucose in older individuals: analysis of the Lothian Birth Cohort of 1936.

AIMS/HYPOTHESIS: The aim of this study was to examine whether cognitive function in early and later life, and decline in cognitive function from age 70 to 79 years, are associated with high blood glucose, as measured by HbA1c, at baseline (age 70), and changes in blood glucose from age 70 to 79. METHODS: Participants (n = 1091) in the Lothian Birth Cohort of 1936 were examined. Fourteen tests were used to assess cognitive functions, grouped into four domains: visuospatial ability, processing speed, memory and crystallised ability. Test results, and measurements of HbA1c and other health variables, were collected at each of four waves of assessment: at the mean age of 70, 73, 76 and 79 years. Data on cognitive function at age 11 was also available for this cohort. Latent growth curve modelling was performed and statistical controls for known risk factors were introduced. RESULTS: Higher age 11 cognitive function predicted lower HbA1c level at age 70 (p < 0.001). Higher cognitive function at age 70 was related to a comparatively smaller increase in HbA1c levels from age 70 to 79 (p < 0.001). HbA1c from age 70 to 79 did not have any consistent association with change in cognitive function from age 70 to 79. These associations survived adjustments for age, sex, education, APOE*ε4, smoking history, cardiovascular disease history, hypertension history, BMI and corrections for multiple testing. CONCLUSIONS/INTERPRETATION: Our results show that, among older individuals, high blood glucose is consistently predicted by lower cognitive function. Clinical care that examines and tracks cognitive function, while also taking the positive effects of maintaining cognitive function and emulating healthy behaviours associated with higher cognitive function into account, may be one approach for protecting at-risk individuals from elevated blood glucose and subsequent type 2 diabetes mellitus.

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.

Widespread associations between trait conscientiousness and thickness of brain cortical regions.

The neural correlates of human personality have been of longstanding interest; however, most studies in the field have relied on modest sample sizes and few replicable results have been reported to date. We investigated relationships between personality and brain gray matter in a sample of generally healthy, older (mean age 73 years) adults from Scotland drawn from the Lothian Birth Cohort 1936. Participants (N = 578) completed a brain MRI scan and self-reported Big Five personality trait measures. Conscientiousness trait scores were positively related to brain cortical thickness in a range of regions, including bilateral parahippocampal gyrus, bilateral fusiform gyrus, left cingulate gyrus, right medial orbitofrontal cortex, and left dorsomedial prefrontal cortex. These associations - most notably in frontal regions - were modestly-to-moderately attenuated by the inclusion of biomarker variables assessing allostatic load and smoking status. None of the other personality traits showed robust associations with brain cortical thickness, nor did we observe any personality trait associations with cortical surface area and gray matter volume. These findings indicate that brain cortical thickness is associated with conscientiousness, perhaps partly accounted for by allostatic load and smoking status.