| 1. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 2. |
- Bogl, Leonie H, et al.
(author)
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Like me, like you - relative importance of peers and siblings on children's fast food consumption and screen time but not sports club participation depends on age.
- 2020
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In: The international journal of behavioral nutrition and physical activity. - : Springer Science and Business Media LLC. - 1479-5868. ; 17:1
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Journal article (peer-reviewed)abstract
- Lifestyle interventions to prevent paediatric obesity often target family and peer settings; their success is likely to depend on the influence that peers and families exert on children's lifestyle behaviors at different developmental stages.First, to determine whether children's lifestyle behavior more closely resembles their peers' or siblings' behaviors. Secondly, to investigate longitudinally whether children's behavioral change is predicted by that of their peers or their siblings as they grow older.The European prospective IDEFICS/I.Family cohort (baseline survey: 2007/2008, first follow-up: 2009/2010, and second follow-up: 2013/2014) aims at investigating risk factors for overweight and related behaviors during childhood and adolescence. The present investigation includes 2694 observations of children and their siblings aged 2 to 18years. Peers were defined as same-sex, same-age children in the same community and identified from the full cohort. The longitudinal analysis (mean follow-up time: 3.7years) includes 525sibling pairs. Children's lifestyle behaviors including fast food consumption (frequency/week), screen time (hours/week) and sports club participation (hours/week) were assessed by questionnaire. Data were analyzed using multilevel linear models.Children's lifestyle behavior was associated with the respective behavior of their peers and sibling for all 3 behaviors. For fast food consumption, the peer resemblance was more than 6-fold higher than the sibling resemblance and the peer resemblance surpassed the sibling resemblance by the age of 9-10years. The similarities with peers for fast food consumption and screen time steadily increased, while the similarities with siblings steadily decreased with increasing age of the children (Pinteraction<0.001). In contrast, the relative importance of peers and siblings on sports club duration did not vary by the age of the children. Longitudinal results showed that children's changes in fast food consumption were more strongly associated with those in their peer group than their sibling, in particular if the age gap between siblings was large.In conclusion, our results support the implementation of multi-setting interventions for improving lifestyle behaviors in children. Our findings might also guide future intervention studies in the choice of timing and setting in which interventions are likely to be most effective. From the ages of 9-10years onwards, family- or home-based interventions targeting children's fast food intake and screen time behavior may become less effective than school- or community-based interventions aimed at peer groups.
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| 3. |
- Erzurumluoglu, A. Mesut, et al.
(author)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Journal article (peer-reviewed)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 4. |
- Hannon, Eilis, et al.
(author)
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DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
- 2021
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In: eLIFE. - : eLife Sciences Publications. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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| 5. |
- Lee, Crystal, et al.
(author)
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Association of anthropometry and weight change with risk of dementia and its major subtypes: a meta-analysis consisting 2.8 million adults with 57,294 cases of dementia
- 2020
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In: Obesity Reviews. - : Wiley. - 1467-7881 .- 1467-789X. ; 21:4
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Journal article (peer-reviewed)abstract
- Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5–22.4 kg/m2), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5–24.9 kg/m2) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had non-significant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change and dementia is complex and exhibits nonlinear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.
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| 6. |
- Li, Chen, et al.
(author)
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Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
- 2020
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In: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 106:3, s. 389-404
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Journal article (peer-reviewed)abstract
- Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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| 7. |
- Mehlig, Kirsten, 1964, et al.
(author)
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Weight status and BMI-related traits in adolescent friendship groups and role of sociodemographic factors: The european IDEFICS/I.family cohort
- 2021
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In: Obesity Facts. - : S. Karger AG. - 1662-4025 .- 1662-4033. ; 14:1, s. 121-130
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Journal article (peer-reviewed)abstract
- © 2020 Background: During adolescence, health behaviors and weight status are increasingly influenced by friendship and peer networks. This paper examines resemblances in weight-related characteristics and how they differ by sociodemographic factors. Methods: Over 3,000 friendships were reported by 1,603 adolescents, aged 11-16 years, who participated in the school-based I.Family study in 6 European countries. Each "source child"named 1-10 friends for whom standardized weight-related traits were available in the same survey. The mean value of the friends' traits weighted by time spent together was calculated, and related to the source child's trait. Country, age and sex of the source child, parental education, and immigrant background were considered for confounding and moderation. Results: Source children's z-scores of body fat percent and BMI were positively associated with their friends' characteristics, in particular if they had highly educated parents. Positive associations were also found regarding the frequency of fast-food consumption, impulsivity, screen time, preference for sugar-sweetened foods, and hours spent in sports clubs, in increasing order of effect size. Additionally, correlations were observed between friends' cognitive and school functioning and being bullied. No associations were seen for a preference for high-fat foods, weight concerns, and health-related quality of life. Finally, parental education and immigrant background were associated between friends in all countries except Sweden, where no associations were observed. Conclusion: Adolescent friends shared a number of weight-related characteristics. For weight measures per se, positive associations with friends' characteristics were only observed in adolescents with high parental education. Associations regarding energy-balance behaviors and indicators of school-related well-being did not differ by parental education. Parental education and immigrant background correlated positively in friends in most countries showing that social aggregation is already occurring in adolescence. The wide spectrum of friendship associations in weight-related traits and behaviors suggests that health promotion initiatives in adolescents should be directed towards peer groups in both school-related and leisure-time environments.
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| 8. |
- Silventoinen, Karri, et al.
(author)
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Genetic and environmental variation in educational attainment : an individual-based analysis of 28 twin cohorts
- 2020
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural–geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41–0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30–0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900–1949 (a2 = 0.44; 0.41–0.46) than in the later cohorts born in 1950–1989 (a2 = 0.38; 0.36–0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29–0.33 and c2 = 0.34; 0.32–0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
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| 9. |
- Stahlmann, Katharina, et al.
(author)
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A cross-sectional study of obesogenic behaviours and family rules according to family structure in European children.
- 2020
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In: The international journal of behavioral nutrition and physical activity. - : Springer Science and Business Media LLC. - 1479-5868. ; 17:1
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Journal article (peer-reviewed)abstract
- There has been an increase in children growing up in non-traditional families, such as single-parent and blended families. Children from such families have a higher prevalence of obesity and poorer health outcomes, but research onthe relationship with obesogenic behaviours is limited.Therefore, the aim of this study was to investigate whether there are associations between family structures and obesogenic behaviours and related family rules in European children and adolescents.The sample included 7664 children (mean age±SD: 10.9±2.9) from 4923 families who were participants of the multi-centre I.Family study (2013/2014) conducted in 8 European countries. Family structure was assessed by a detailed interview on kinship and household. Obesogenic behaviours (screen time, sleep duration, consumption of sugar-sweetened beverages (SSBs)) and family rules (rules for computer and television, bedtime routine, availability of SSBs during meals) were determined by standardized questionnaires. Multilevel mixed-effects linear and logistic regression models were used to model the associations of family structure with obesogenic behaviours and family rules. Sex, age, parental education level, number of children and adults in the household and BMI z-score were covariates in the models. Two-parent biological families were set as the reference category.Children from single-parent families were less likely to have family rules regarding screen time (OR: 0.62, 95% CI: 0.40-0.94, p=0.026) with higher reported hours of screen time per week (β=2.70h/week, 95% CI: 1.39-4.00, p<0.001). The frequency of weekly SSB consumption differed by family structure in a sex-specific manner: girls from single-parent (β=3.19 frequency/week, 95% CI: 0.91-5.47, p=0.006) and boys from blended/adoptive families (β=3.01 frequency/week, 95% CI: 0.99-5.03, p=0.004) consumed more SSBs. Sleep duration, bedtime routines and availability of SSBs during meals did not differ between children from these family structures. Parental education did not modify any of these associations.Parents in non-traditional family structures appear to experience more difficulties in restricting screen time and the intake of SSBs in their children than parents in traditional two-parent family structures. Our findings therefore suggest that additional support and effective strategies for parents in non-traditional families may help to reduce obesogenic behaviours in children from such family types.
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| 10. |
- van der Kolk, Birgitta W., et al.
(author)
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Molecular pathways behind acquired obesity : Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI
- 2021
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In: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 2:4, s. 100226-
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Journal article (peer-reviewed)abstract
- Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
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