31 research outputs found
Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development
Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D
Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.Peer reviewe
The effect of improvisational music therapy on the treatment of depression: protocol for a randomised controlled trial
Background.
Music therapy is frequently offered to individuals suffering from depression. Despite the lack of research into the effects of music therapy on this population, anecdotal evidence suggests that the results are rather promising. The aim of this study is to examine whether improvisational, psychodynamically orientated music therapy in an individual setting helps reduce symptoms of depression and improve other health-related outcomes. In particular, attention will be given to mediator agents, such as musical expression and interaction in the sessions, as well as to the explanatory potential of EEG recordings in investigating emotion related music perception of individuals with depression.
Methods.
85 adults (18–50 years of age) with depression (ICD-10: F 32 or F33) will be randomly assigned to an experimental or a control condition. All participants will receive standard care, but the experimental group will be offered biweekly sessions of improvisational music therapy over a period of 3 months. A blind assessor will measure outcomes before testing, after 3 months, and after 6 months.
Discussion.
This study aims to fill a gap in knowledge as to whether active (improvisational) music therapy applied to people with depression improves their condition. For the first time in this context, the mediating processes, such as changes in musical expression and interaction during the course of therapy, will be objectively investigated, and it is expected that the results will provide new insights into these processes. Furthermore, the findings are expected to reveal whether music related emotional experiences, as measured by EEG, can be utilized in assessing a depressive client's improvement in the therapy. The size and the comprehensiveness of the study are sufficient for generalizing its findings to clinical practice as well as to further music therapy research.
Trial registration.
ISRCTN84185937peerReviewe
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training
5-T32-GM007748-33
Doris Duke Charitable Foundation
2006087
Fulbright Diabetes UK Fellowship
BDA 11/0004348
Broad Institute from Pfizer, Inc.
NIH
U01 DK085501
U01 DK085524
U01 DK085545
U01 DK085584
Swedish Research Council
Dnr 521-2010-3490
Dnr 349-2006-237
European Research Council (ERC)
GENETARGET T2D
GA269045
ENGAGE
2007-201413
CEED3
2008-223211
Sigrid Juselius Foundation
Folkh lsan Research Foundation
ERC
AdG 293574
Research Council of Norway
197064/V50
KG Jebsen Foundation
University of Bergen
Western Norway Health Authority
Lundbeck Foundation
Novo Nordisk Foundation
Wellcome Trust
WT098017
WT064890
WT090532
WT090367
WT098381
Uppsala University
Swedish Research Council and the Swedish Heart- Lung Foundation
Academy of Finland
124243
102318
123885
139635
Finnish Heart Foundation
Finnish Diabetes Foundation, Tekes
1510/31/06
Commission of the European Community
HEALTH-F2-2007-201681
Ministry of Education and Culture of Finland
European Commission Framework Programme 6 Integrated Project
LSHM-CT-2004-005272
City of Kuopio and Social Insurance Institution of Finland
Finnish Foundation for Cardiovascular Disease
NIH/NIDDK
U01-DK085545
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Minority Health and Health Disparities
N01 HC-95170
N01 HC-95171
N01 HC-95172
European Union Seventh Framework Programme, DIAPREPP
Swedish Child Diabetes Foundation (Barndiabetesfonden)
5U01DK085526
DK088389
U54HG003067
R01DK072193
R01DK062370
Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease
The genetic architecture of type 2 diabetes
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Peer reviewe
Communicating information about the funding of occupational pension schemes to scheme members
SIGLEAvailable from British Library Document Supply Centre- DSC:4372. 252(110) / BLDSC - British Library Document Supply CentreGBUnited Kingdo