| 1. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
|
|
| 2. |
- Justice, A. E., et al.
(författare)
-
Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
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.
|
|
| 3. |
- Graff, M., et al.
(författare)
-
Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
-
Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
-
Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
|
|
| 4. |
|
|
| 5. |
- Willems, S. M., et al.
(författare)
-
Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
- 2017
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
|
|
| 6. |
|
|
| 7. |
- Palmer, Nicholette D, et al.
(författare)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Kinyoki, DK, et al.
(författare)
-
Mapping child growth failure across low- and middle-income countries
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 577:7789, s. 231-
-
Tidskriftsartikel (refereegranskat)abstract
- Childhood malnutrition is associated with high morbidity and mortality globally1. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood2. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0–59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards3–5. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization’s median growth reference standards for a healthy population6. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces)7; the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes8. Building from our previous work mapping CGF in Africa9, here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live1, aggregated to policy-relevant first and second (for example, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications.
|
|
