633 research outputs found
Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes
Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © 2015 by the American Diabetes Association.This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-1710/-/DC1.The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (ÎČ = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (ÎČ = -0.21, P = 5 Ă 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.Knut and Alice Wallenberg FoundationERCSwedish Research CouncilFredrik och Ingrid Thurings StiftelseSwedish Heart-Lung Foundationacknowledges SydvĂ€stra SkĂ„nes DiabetesföreningNovo Nordisk FoundationUniversity of TartuEuropean Foundation for the Study of Diabetes New HorizonsAmerican Heart Associatio
Subjective Well-Being Under Neuroleptics Scale short form (SWN-K):Reliability and validity in an Estonian speaking sample
BACKGROUND: The Subjective Well-Being Under Neuroleptic Treatment Scale short form (SWN-K) is a self-rating scale developed to measure mentally ill patients' well-being under the antipsychotic drug treatment. This paper reports on adaptation and psychometric properties of the instrument in an Estonian psychiatric sample. METHODS: In a naturalistic study design, 124 inpatients or outpatients suffering from the first psychotic episode or chronic psychotic illness completed the translated SWN-K instrument. Item content analysis, internal consistency analysis, exploratory principal components analysis, and confirmatory factor analysis were used to construct the Estonian version of the SWN-K (SWN-K-E). Additionally, socio-demographic and clinical data, observer-rated psychopathology, medication side effects, daily antipsychotic drug dosages, and general functioning were assessed at two time points, at baseline and after a 29-week period; the associations of the SWN-K-E scores with these variables were explored. RESULTS: After having selected 20 items for the Estonian adaptation, the internal consistency of the total SWN-K-E was 0.93 and the subscale consistencies ranged from 0.70 to 0.80. Good testâretest reliabilities were observed for the adapted scale scores, with the correlation of the total score over about 6 months being r = 0.70. Confirmatory factor analysis replicated the presence of a higher-order factor (general well-being) and five first-order factors (mental functioning, physical functioning, social integration, emotional regulation, and self-control); the model fitted the data well. The results indicated a moderate-high correlations r = 0.54 between the SWN-K-E total score and the evaluation how satisfied patients were with their lives in generally. No significant correlations were found between the overall subjective well-being score and age, severity of the psychopathology, drug adverse effects, or prescribed drug dosage. CONCLUSION: Taken together, the results demonstrated that the Estonian version of the SWN-K is a reliable and valid instrument with psychometric properties similar to the original English version. The potential uses of the scale in both research and clinical settings are considered
A new model of how celebrity endorsements work: attitude toward the endorsement as a mediator of celebrity source and endorsement effects
This research introduces attitude towards the endorsement as a mediating variable in the relationships between celebrity source and endorsement factors and brand attitude. It also includes perceived celebrity motive, a variable rarely studied in the previous literature, as an endorsement factor. In a survey study, respondents evaluated four celebrity endorsement campaigns. Mediation analyses show that attitude towards the endorsement mediates the effects of three variables on brand attitude; these variables are celebrity expertise, celebrityâbrand fit, and perceived celebrity motive. Moreover, results show that if consumers perceive that the celebrity was motivated to do the endorsement not only by money but also by product quality, this has a significant positive effect on attitude towards the brand
Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes
Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets
SCOPA and META-SCOPA: software for the analysis and aggregation of genome-wide association studies of multiple correlated phenotypes
Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways
OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels.
RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.
RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 Ă 10â26), HFE (rs1800562/P = 2.6 Ă 10â20), TMPRSS6 (rs855791/P = 2.7 Ă 10â14), ANK1 (rs4737009/P = 6.1 Ă 10â12), SPTA1 (rs2779116/P = 2.8 Ă 10â9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 Ă 10â9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 Ă 10â54), MTNR1B (rs1387153/P = 4.0 Ă 10â11), GCK (rs1799884/P = 1.5 Ă 10â20) and G6PC2/ABCB11 (rs552976/P = 8.2 Ă 10â18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify âŒ2% of a general white population screened for diabetes with HbA1c.
CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c
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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2âmillion individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures
Copy number variations and cognitive phenotypes in unselected populations
IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear.
OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency â€0.05%; size â„250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population.
DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy.
MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability.
RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, â€0.05%; â„250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (Pâ=â1.06e-04) among 248 (â„250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (â„1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; Pâ=â.005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; Pâ=â1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom.
CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health
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