| 1. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Jang, Seon-Kyeong, et al.
(författare)
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Rare genetic variants explain missing heritability in smoking.
- 2022
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 6:11, s. 1577-1586
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Tidskriftsartikel (refereegranskat)abstract
- Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
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| 4. |
- Nielson, Carrie M., et al.
(författare)
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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2
- 2016
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 31:12, s. 2085-2097
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (β=0.22, p=1.9×10-8) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (β=0.09, p=1.2×10-10) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10-4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β=0.12, FDR p=1.7×10-3, functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence.
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| 5. |
- Boone, Sebastiaan C., et al.
(författare)
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Evaluation of the Value of Waist Circumference and Metabolomics in the Estimation of Visceral Adipose Tissue
- 2022
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 191:5, s. 886-899
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Tidskriftsartikel (refereegranskat)abstract
- Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008-2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R-2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm(2) and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R-2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006-2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2007). Performance was comparable to the development setting in PIVUS (R-2 = 0.63, RMSE = 42.4 cm(2), calibration slope = 0.94) but lower in MESA (R-2 = 0.44, RMSE = 60.7 cm(2), calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.
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| 6. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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| 7. |
- Thanassoulis, George, et al.
(författare)
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Genetic Associations with Valvular Calcification and Aortic Stenosis
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 368:6, s. 503-512
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Tidskriftsartikel (refereegranskat)abstract
- Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
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| 8. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 9. |
- Szalo, Gabor, et al.
(författare)
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Longitudinal association between leisure-time physical activity and vascular elasticity indices
- 2021
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- AimWe investigated the association between levels of leisure-time physical activity and vascular stiffness in a longitudinal observational study from a representative Swedish population.MethodA total of 2816 randomly selected individuals were examined at visit 1 (2002-2005, Men=1400). After a mean follow-up of 9.71.4 years, a representative sample of 1327 of the original participants were re-examined at visit 2. After excluding subjects with hypertension at baseline, 761 participants were included in the longitudinal analyses. Leisure-time physical (LTPA) activity was self-reported and dichotomized as high or low (level 3, 4 and level 1, 2, respectively). Large Arterial Elasticity Index (LAEI) and Small Arterial Elasticity Index (SAEI) were measured using the HDI/Pulse Wave (TM) CR2000. Multivariable general linear models were used to investigate the differences in changes SAEI and LAEI based on LTPA levels.ResultsAt visit 1, and after adjustment for possible confounders, participants in the high LTPA group had better small artery elasticity (SAEI) (SAEI in low-level LTPA: 7.89 +/- 0.11, SAEI in high-level LTPA: 8.32 +/- 0.15, Delta SAEI: 0.42, CI: 0.07-0.78; p=0.020). SAEI decreased between the two assessments (Visit 1: SAEI 8.01 +/- 3.37 ml/mmHg; Delta SAEI: 1.4, CI 1.2-1.6, p<0.001). Participants with a higher LTPA at visit 1 had significantly better SAEI at visit 2 (SAEI: 0.44, CI 0.03-0.85, p=0.037). No significant associations were observed between LAEI and LTPA after adjustments.Conclusions High LTPA predicted higher small arterial compliance at visit 2 suggesting that positive effects of LTPA on arterial elasticity persists over time.
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| 10. |
- Lau, Allison N., et al.
(författare)
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Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
- 2020
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Ingår i: eLife. - 2050-084X. ; 9, s. 1-35
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Tidskriftsartikel (refereegranskat)abstract
- Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.
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