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- Justice, A. E., et al.
(författare)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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| 7. |
- Zillikens, M. C., et al.
(författare)
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
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| 8. |
- Lee, James J, et al.
(författare)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
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Tidskriftsartikel (refereegranskat)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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- Cawthon, P. M., et al.
(författare)
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Putative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: AnSDOCAnalysis
- 2020
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Ingår i: Journal of the American Geriatrics Society. - : Wiley. - 0002-8614 .- 1532-5415. ; 68:7, s. 1429-1437
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht(2)); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality). DESIGN Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 +/- 2.3 years for mortality. SETTING Eight prospective observational cohort studies. PARTICIPANTS A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA. RESULTS Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness. CONCLUSION Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia.
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| 10. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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