| 1. |
- Lango Allen, Hana, et al.
(author)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Journal article (peer-reviewed)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 2. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 3. |
- Allesøe, Rosa Lundbye, et al.
(author)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Journal article (peer-reviewed)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 4. |
- Geidenstam, Nina, et al.
(author)
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Amino Acid Signatures to Evaluate the Beneficial Effects of Weight Loss
- 2017
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In: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2017
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Journal article (peer-reviewed)abstract
- Aims. We investigated the relationship between circulating amino acid levels and obesity; to what extent weight loss followed by weight maintenance can correct amino acid abnormalities; and whether amino acids are related to weight loss. Methods. Amino acids associated with waist circumference (WC) and BMI were studied in 804 participants from the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Changes in amino acid levels were analyzed after weight loss and weight maintenance in 12 obese subjects and evaluated in a replication cohort (n = 83). Results. Out of the eight identified BMI-associated amino acids from the MDC-CC, alanine, isoleucine, tyrosine, phenylalanine, and glutamate decreased after weight loss, while asparagine increased after weight maintenance. These changes were validated in the replication cohort. Scores that were constructed based on obesity-associated amino acids and known risk factors decreased in the ≥10% weight loss group with an associated change in BMI (R(2) = 0.16-0.22, p < 0.002), whereas the scores increased in the <10% weight loss group (p < 0.0004). Conclusions. Weight loss followed by weight maintenance leads to differential changes in amino acid levels associated with obesity. Treatment modifiable scores based on epidemiological and interventional data may be used to evaluate the potential metabolic benefit of weight loss.
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| 5. |
- Johansson, Lovisa, et al.
(author)
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Variation in the adiponutrin gene influences its expression and associates with obesity.
- 2006
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:3, s. 826-833
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Journal article (peer-reviewed)abstract
- Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.
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| 6. |
- Aghili, Rokhsareh, et al.
(author)
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Psychosocial factors and glycemic control in insulin-naïve and insulin-experienced people with type 2 diabetes : a path analysis model
- 2018
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In: International Journal of Diabetes in Developing Countries. - : Springer Science and Business Media LLC. - 0973-3930 .- 1998-3832. ; 38:3, s. 289-297
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Journal article (peer-reviewed)abstract
- The purpose of this study was to compare the status of psychosocial factors and glycemic control in insulin-naïve and insulin-experienced people with type 2 diabetes (T2D). In this observational study on people with T2D, demographic, self-care behavior, resources, and affective variables as well as health-related quality of life were assessed and compared in insulin-naïve and insulin-experienced considering the number of oral glucose-lowering drugs (OGLDs). Measured variable path analysis was used to test the association among variables and their effect on HbA1c in both groups. In total, 215 insulin-naïve and 165 insulin-experienced patients were recruited in this study. The mean duration of diabetes was 11.7 ± 7.0 years in insulin-experienced and 6.8 ± 5.4 years in insulin-naïve (p < 0.001). The mean hemoglobin A1c (HbA1c) was significantly higher in insulin-experienced subjects irrespective of the number of OGLDs [68 ± 20 mmol/mol (8.4 ± 1.8%) vs. 56 ± 16 mmol/mol (7.3 ± 1.4%); p < 0.001]. Moreover, insulin-experienced subjects had significantly higher level of diabetes-related distress (2.2 ± 0.9 vs. 1.9 ± 0.8), depression (9.5 ± 5.5 vs. 8.1 ± 5.1), anxiety (18.3 ± 12.0 vs. 15.1 ± 10.5), and lower knowledge of insulin use considering the results of 9-item insulin-use subscale of Michigan diabetes knowledge test (mean 3.9 ± 1.8) compared to insulin-naïve subjects (p < 0.05). Higher levels of distress, depression, and anxiety are found in insulin-experienced people with T2D. Therefore, one should be aware that, at the time of insulin need/initiation, people with T2D have reached a more vulnerable state and this should be taken into consideration when implementing a complex insulin initiation plan.
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| 7. |
- Aghili, Rokhsareh, et al.
(author)
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The challenge of living with diabetes in women and younger adults : A structural equation model
- 2017
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In: Primary Care Diabetes. - : Elsevier BV. - 1751-9918. ; 11:5, s. 467-473
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Journal article (peer-reviewed)abstract
- Background: Attitudes toward diabetes care are different between genders and age-groups. Furthermore, diabetes related challenges may cause psychosocial problems. Therefore, we were to compare the psychosocial status and glycemic control in women and men with type 2 diabetes (T2D) in different age-groups. Methods: 441 adults with T2D were recruited. Demographic, self-care behavior, resources and affective variables as well as the health related quality of life (HRQoL) were measured. The median age of 55 was used as the cut-off for the age comparison. Structured equation modeling (SEM) investigated the relationship between age, gender, psychosocial factors and glycemic control. Results: Finally, 203 women and 177 men completed the study (86.1%). There was no significant difference in mean duration of T2D, or glycemic control between genders or age-groups. Women, especially those below the median age of 55, had significantly higher level of diabetes-related distress (2.16. ±. 0.94 vs. 1.92. ±. 0.81), depression (9.67. ±. 5.37 vs. 7.54. ±. 5.06), and anxiety (19.81. ±. 12.04 vs. 12.81. ±. 9.04, P. <. 0.05 for all comparisons), while people above the age of 55 reported better self-management and patient-physician relationship. HRQoL was lower in women compared to men (0.77. ±. 0.23 vs. 0.81. ±. 0.18, P = 0.02). The final SEM suggested that the effect (standardized β coefficient) of gender and age on affective variables was 0.25 and -0.19 (P. <. 0.05), respectively, though psychosocial factors did not directly influence HbA1c. Conclusions: This study shows that psychosocial factors are associated with age and gender in patients with T2D; with younger women demonstrating higher level of depressive symptoms, anxiety, and diabetes-related distress independent of status of glycemic control.
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| 8. |
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| 9. |
- Ahlzén, Maja, et al.
(author)
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Expression of the transcription factor 7-like 2 gene (TCF7L2) in human adipocytes is down regulated by insulin.
- 2008
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 370, s. 49-52
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Journal article (peer-reviewed)abstract
- Variants in the TCF7L2 gene (transcription factor 7-like 2) have shown strong association with type 2 diabetes with two defined risk haplotypes, HapA and HapB(T2D). TCF7L2 may play a role in both glucose homeostasis and adipogenesis. Our aim was to characterize the TCF7L2 mRNA expression and regulation in human adipose tissue. We quantified TCF7L2 mRNA levels in cultured human adipocytes and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissue from 38 obese non-diabetic subjects, using real-time PCR. The influence of haplotype and clinical traits on TCF7L2 mRNA levels were investigated. In vitro, insulin decreased TCF7L2 mRNA expression. This effect was attenuated in cells incubated with the free fatty acids palmitate or oleate. In vivo, we found significantly higher expression in SAT from more insulin resistant subjects. No correlations between TCF7L2 mRNA expression and obesity measures were observed. TCF7L2 expression was higher in VAT than in SAT and when stratifying for haplotype, this difference was seen in HapA carriers but not in non-HapA carriers. In conclusion, TCF7L2 mRNA levels in adipocytes are decreased by insulin and seem to increase in insulin resistant subjects and in HapA carriers.
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| 10. |
- Amisten, Stefan, et al.
(author)
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The P2Y(13) Met-158-Thr Polymorphism, Which Is in Linkage Disequilibrium with the P2Y(12) Locus, Is Not Associated with Acute Myocardial Infarction.
- 2008
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:1
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: The aims of this study were to investigate (1) if P2Y(12) polymorphisms defining the P2Y(12) H2 allele are associated with any other SNPs that may explain the previously reported association with increased ADP induced platelet activation and association with peripheral arterial disease and coronary artery disease and (2) if such variants are associated with acute myocardial infarction (AMI) or classical risk factors for AMI. METHODS AND RESULTS: The P2Y(13) Met-158-Thr polymorphism was found to be in linkage disequilibrium (LD) with the P2Y(12) H2 haplotype (all examined SNPs: D' = 1.0, r(2) = 0.936-1.0), defining a novel P2Y(12) H2/P2Y(13) Thr-158 haplotype. Genotyping of an AMI case control population (n = 1244 cases, 2488 controls) revealed no association of the P2Y(13) Thr-158 allele with AMI (OR = 0.96, 95% C.I. 0.82-1.12, P = 0.63). Also, no differences between the genotype frequencies of P2Y(13) Met-158-Met and Met-158-Thr/Thr-158-Thr were seen in AMI case-control subpopulations (early onset AMI OR = 1.06, 95% C.I. 0.85-1.31, P = 0.62); family history of AMI (OR = 0.98, 95% C.I. 0.78-1.22, P = 0.83) nor in early onset AMIs with family history of AMI (OR = 1.0, 95% C.I. 0.74-1.36, P = 1.0). Genotyping of the P2Y(13) Met-158-Thr polymorphism in a population based sample (n = 6055) revealed no association with cardiovascular risk factors. In addition, the P2Y(13) Met-158-Thr polymorphism was genotyped in a diabetes case-control population, and associations were found neither with DM nor with any examined DM risk factors. CONCLUSION GENOTYPING: The P2Y(13) Met-158-Thr polymorphism is in tight LD with the P2Y(12) locus but is not associated with AMI or classical cardiovascular risk factors.
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