Dataset Information

Insulin resistance: Genetic associations with depression and cognition in population based cohorts.

ABSTRACT: Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition.

SUBMITTER: Frangou S

PROVIDER: S-EPMC6503941 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Insulin resistance: Genetic associations with depression and cognition in population based cohorts.

Frangou Sophia S Shirali Masoud M Adams Mark J MJ Howard David M DM Gibson Jude J Hall Lynsey S LS Smith Blair H BH Padmanabhan Sandosh S Murray Alison D AD Porteous David J DJ Haley Chris S CS Deary Ian J IJ Clarke Toni-Kim TK McIntosh Andrew M AM

Experimental neurology 20190406

Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifi ...[more]

PMID: 30965038

Similar Datasets

Project description:Aims/hypothesisOur study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance.MethodsFasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at ∼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load.ResultsPer-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (β = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect.Conclusions/interpretationThe present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.

Project description:IntroductionPrimary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting salivary and lacrimal glands, while endometriosis involves uterine-like tissue growth outside the uterus, causing pelvic pain and infertility. Investigating their intricate relationship using real-world data is crucial due to limited research on their connection.Material and methodsThis population-based cohort study included patients with endometriosis and controls without endometriosis. Propensity score matching was used to balance baseline differences in demographic and clinic characteristics between the two groups. Cox proportional hazards model were used to estimate the effect of endometriosis on the risk of new-onset pSS over time. A symmetrical cohort study, including patients with pSS and propensity score-matched controls without pSS, was conducted to investigate the effect of pSS on the risk of endometriosis over time. To elaborate on the mechanisms linking endometriosis and pSS, Ingenuity Pathway Analysis was performed to identify activated pathways in eutopic endometrium from patients with endometriosis and parotid tissues from patients with pSS.ResultsA total of 15 947 patients with endometriosis and 15 947 propensity score-matched controls without endometriosis were included. Patients with endometriosis presented a significantly greater risk of pSS compared to non-endometriosis controls (adjusted hazard ratio, aHR = 1.57, 95% CI = 1.29-1.91, p < 0.001). In the symmetrical cohort study, which included 4906 pSS patients and 4,906 propensity score-matched controls without pSS, patients with pSS were found to be at a significantly higher risk of endometriosis compared to non-pSS controls (aHR = 1.51, 95% CI = 1.12-2.04, p = 0.012). Ingenuity Pathway Analysis showed that the underlying cellular mechanisms involved autoimmune-related pathways, including activation of dendritic cell maturation, and chronic inflammatory pathways, including the fibrosis signaling pathway.ConclusionsThese findings support a bidirectional association between endometriosis and pSS, which may be driven by dendritic cell maturation and fibrosis signaling pathways.

Project description:BackgroundThe 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and the Sarcopenia Definitions and Outcomes Consortium (SDOC) have recently proposed sarcopenia definitions. However, comparisons of the performance of these approaches in terms of thresholds employed, concordance in individuals and prediction of important health-related outcomes such as death are limited. We addressed this in a large multinational assembly of cohort studies that included information on lean mass, muscle strength, physical performance and health outcomes.MethodsWhite men from the Health Aging and Body Composition (Health ABC) Study, Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, USA), the Hertfordshire Cohort Study (HCS) and the Sarcopenia and Physical impairment with advancing Age (SarcoPhAge) Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over courses of 2.4-6 m. Deaths were recorded and verified. Definitions of sarcopenia were as follows: EWGSOP2 (grip strength <27 kg and ALM index <7.0 kg/m2 ), SDOC (grip strength <35.5 kg and gait speed <0.8 m/s) and Modified SDOC (grip strength <35.5 kg and gait speed <1.0 m/s). Cohen's kappa statistic was used to assess agreement between original definitions (EWGSOP2 and SDOC). Presence versus absence of sarcopenia according to each definition in relation to mortality risk was examined using Cox regression with adjustment for age and weight; estimates were combined across cohorts using random-effects meta-analysis.ResultsMean (SD) age of participants (n = 9170) was 74.3 (4.9) years; 5929 participants died during a mean (SD) follow-up of 12.1 (5.5) years. The proportion with sarcopenia according to each definition was EWGSOP2 (1.1%), SDOC (1.7%) and Modified SDOC (5.3%). Agreement was weak between EWGSOP2 and SDOC (κ = 0.17). Pooled hazard ratios (95% CI) for mortality for presence versus absence of each definition were EWGSOP2 [1.76 (1.42, 2.18), I2 : 0.0%]; SDOC [2.75 (2.28, 3.31), I2 : 0.0%]; and Modified SDOC [1.93 (1.54, 2.41), I2 : 58.3%].ConclusionsThere was low prevalence and poor agreement among recent sarcopenia definitions in community-dwelling cohorts of older white men. All indices of sarcopenia were associated with mortality. The strong relationship between sarcopenia and mortality, regardless of the definition, illustrates that identification of appropriate management and lifecourse intervention strategies for this condition is of paramount importance.

Dataset Information

Insulin resistance: Genetic associations with depression and cognition in population based cohorts.

Publications

Insulin resistance: Genetic associations with depression and cognition in population based cohorts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets