| 1. |
- Lind, Lars, et al.
(author)
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Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)
- 2021
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In: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
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| 2. |
- Bixby, H., et al.
(author)
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Rising rural body-mass index is the main driver of the global obesity epidemic in adults
- 2019
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 569:7755, s. 260-4
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Journal article (peer-reviewed)abstract
- Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
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| 3. |
- Mishra, A, et al.
(author)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Journal article (peer-reviewed)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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| 4. |
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| 5. |
- Ramdas, S., et al.
(author)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Journal article (peer-reviewed)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 6. |
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| 7. |
- Graff, M., et al.
(author)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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In: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Journal article (peer-reviewed)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.
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| 8. |
- Taddei, C, et al.
(author)
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Repositioning of the global epicentre of non-optimal cholesterol
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 582:7810, s. 73-
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Journal article (peer-reviewed)abstract
- High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
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| 9. |
- Justice, A. E., et al.
(author)
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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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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)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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| 10. |
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| 11. |
- Wang, Z., et al.
(author)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
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Journal article (peer-reviewed)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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| 21. |
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| 22. |
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| 23. |
- Pulit, S. L., et al.
(author)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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In: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Journal article (peer-reviewed)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 26. |
- Bryois, J., et al.
(author)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 29. |
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| 30. |
- Ip, H. F., et al.
(author)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Journal article (peer-reviewed)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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| 31. |
- Shrine, N, et al.
(author)
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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
- 2023
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 55:3, s. 410-
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Journal article (peer-reviewed)abstract
- Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
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| 32. |
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| 33. |
- Ahluwalia, T. S., et al.
(author)
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Genome-wide association study of circulating interleukin 6 levels identifies novel loci
- 2021
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In: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:5, s. 393-409
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Journal article (peer-reviewed)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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| 34. |
- Bentham, James, et al.
(author)
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A century of trends in adult human height
- 2016
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In: eLIFE. - 2050-084X. ; 5
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Journal article (peer-reviewed)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 35. |
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| 36. |
- Nolte, I. M., et al.
(author)
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Genetic loci associated with heart rate variability and their effects on cardiac disease risk
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
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| 37. |
- van Bragt, JJMH, et al.
(author)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Journal article (peer-reviewed)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 44. |
- Jami, E. S., et al.
(author)
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Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms
- 2022
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In: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier BV. - 0890-8567 .- 1527-5418. ; 61:7, s. 934-945
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Journal article (peer-reviewed)abstract
- Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.
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| 45. |
- Jiang, X., et al.
(author)
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Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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| 48. |
- Winkler, TW, et al.
(author)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Journal article (peer-reviewed)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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