| 1. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 2. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 3. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 4. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 5. |
- Sung, Yun Ju, et al.
(författare)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 6. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 7. |
- Crema, Michel D, et al.
(författare)
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Factors Associated with Meniscal Extrusion in Knees with or at Risk for Osteoarthritis: The Multicenter Osteoarthritis Study.
- 2012
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 264:2, s. 494-503
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess the associations of meniscal tears, knee malalignment, cartilage damage, knee effusion, and body mass index with meniscal extrusion. Materials and Methods: The Multicenter Osteoarthritis study is an observational study of individuals who have or are at risk for knee osteoarthritis (OA). The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all patients. All subjects with available baseline knee radiographs and magnetic resonance (MR) images were included. MR imaging assessment of meniscal morphologic characteristics, meniscal position, and cartilage morphologic characteristics with use of the Whole-Organ Magnetic Resonance Imaging Score system was performed by two musculoskeletal radiologists. Cross-sectional associations of severity of meniscal tears, knee malalignment, tibiofemoral cartilage damage, knee effusion, and body mass index with meniscal extrusion were assessed by using logistic regression, with multiadjustments when testing each predictor. Results: A total of 1527 subjects (2131 knees; 2116 medial and 2106 lateral menisci) were included. Medially, meniscal tears, varus malalignment, and cartilage damage were associated with meniscal extrusion, with odds ratios (ORs) of 6.3 (95% confidence interval [CI]: 5.0, 8.0), 1.3 (95% CI: 1.1, 1.7), and 1.8 (95% CI: 1.4, 2.2), respectively. Laterally, meniscal tears, valgus malalignment, and cartilage damage were associated with meniscal extrusion, with ORs of 10.3 (95% CI: 7.1, 14.9), 2.2 (95% CI: 1.5, 3.2), and 2.0 (95% CI: 1.3, 2.9), respectively. Conclusion: Meniscal tears are not the only factors associated with meniscal extrusion; other factors include knee malalignment and cartilage damage. Meniscal extrusion is probably an effect of the complex interactions among joint tissues and mechanical stresses involved in the OA process.© RSNA, 2012.
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| 8. |
- Englund, Martin, et al.
(författare)
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Meniscal pathology on MRI increases the risk for both incident and enlarging subchondral bone marrow lesions of the knee: the MOST Study.
- 2010
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; May 4, s. 1796-1802
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: /st> To investigate the association between meniscal pathology and incident or enlarging bone marrow lesions (BML) in knee osteoarthritis. METHODS: /st> The authors studied subjects from the Multicenter Osteoarthritis Study aged 50-79 years either with knee osteoarthritis or at high risk of the disease. Baseline and 30-months magnetic resonance images of knees (n=1344) were scored for subchondral BML. Outcome was defined as an increase in BML score in either the tibial or femoral condyle in medial and lateral compartments, respectively. The authors defined meniscal pathology at baseline as the presence of either meniscal lesions or meniscal extrusion. The risk of an increase in BML score in relation to meniscal status in the same compartment was estimated using a log linear regression model adjusted for age, sex, body mass index, physical activity level and mechanical axis. In secondary analyses the investigators stratified by ipsilateral tibiofemoral cartilage status at baseline and compartments with pre-existing BML. RESULTS: /st> The adjusted relative risk of incident or enlarging BML ranged from 1.8; 95% CI 1.3 to 2.3 for mild medial meniscal pathology to 5.0; 95% CI 3.2 to 7.7 for major lateral meniscal pathology (using no meniscal pathology in the same compartment as reference). Stratification by cartilage or BML status at baseline had essentially no effect on these estimates. CONCLUSIONS: /st> Knee compartments with meniscal pathology have a substantially increased risk of incident or enlarging subchondral BML over 30 months. Higher relative risks were seen in those with more severe and with lateral meniscal pathology.
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| 9. |
- Englund, Martin, et al.
(författare)
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Meniscal Tear in Knees Without Surgery and the Development of Radiographic Osteoarthritis Among Middle-Aged and Elderly Persons The Multicenter Osteoarthritis Study
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 60:3, s. 831-839
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Although partial meniscectomy is a risk factor for the development of knee osteoarthritis (OA), there is a lack of evidence that meniscal damage that is not treated with surgery would also lead to OA, suggesting that surgery itself may cause joint damage. Furthermore, meniscal damage is common. The aim of this study was to evaluate the association between meniscal damage in knees without surgery and the development of radiographic tibiofemoral OA. Methods. We conducted a prospective case-control study nested within the observational Multicenter Osteoarthritis Study, which included a sample of men and women ages 50-79 years at high risk of knee OA who were recruited from the community. Patients who had no baseline radiographic knee OA but in whom tibiofemoral OA developed during the 30-month followup period were cases (n = 121). Control subjects (n = 294) were drawn randomly from the same source population as cases but had no knee OA after 30 months of followup. Individuals whose knees had previously undergone surgery were excluded. Meniscal damage was defined as the presence of any medial or lateral meniscal tearing, maceration, or destruction. Results. Meniscal damage at baseline was more common in case knees than in control knees (54% versus 18%; P < 0.001). The model comparing any meniscal damage with no meniscal damage (adjusted for baseline age, sex, body mass index, physical activity, and mechanical knee alignment) yielded an odds ratio of 5.7 (95% confidence interval 3.4-9.4). Conclusion. In knees without surgery, meniscal damage is a potent risk factor for the development of radiographic OA. These results highlight the need for better understanding, prevention, and treatment of meniscal damage.
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| 10. |
- Englund, Martin, et al.
(författare)
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Risk factors for medial meniscal pathology on knee MRI in older US adults: a multicentre prospective cohort study.
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70, s. 1733-1739
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Meniscal pathology in which the aetiology is often unclear is a frequent finding on knee MRI. This study investigates potential risk factors for medial meniscal lesions or extrusion in middle-aged and elderly persons. METHODS: Prospective cohort study using population-based subjects from Birmingham, Alabama and Iowa City, Iowa, USA (the Multicenter Osteoarthritis Study). 644 men and women aged 50-79 years with or at high risk of knee osteoarthritis (Kellgren and Lawrence grade 0-2) but with normal medial meniscal status at baseline were studied. Paired baseline and 30-month 1.0 T knee MRI were scored for meniscal lesions and extrusion (pathology) and the following systemic, knee-specific and compartment-specific potential risk factors were evaluated: age, sex, body mass index, bony enlargement of finger joints, knee trauma, leg-length inequality and knee alignment. RESULTS: Of 791 knees, 77 (9.7%) had medial meniscal pathology at 30 months follow-up. 61 of the 77 (81%) had no report of trauma during follow-up. Including all potential risk factors in the multivariable model, the adjusted OR for medial meniscal pathology was 4.14 (95% CI 2.06 to 8.31) for knee trauma during follow-up, 1.64 (1.00 to 2.70) for five or more bony enlargements of finger joints (vs ≤4) and 2.00 (1.18 to 3.40) for varus alignment (vs not varus) at baseline examination. Obesity was a risk factor for the development of meniscal extrusion, OR 3.04 (1.04 to 8.93) but not for meniscal lesions, OR 1.15 (0.52 to 2.54). CONCLUSIONS: Apart from knee trauma, possible generalised osteoarthritis, expressed as multiple bony enlargements of finger joints, varus alignment and obesity are risk factors for medial meniscal pathology.
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