A longitudinal study of eating behaviours in childhood and later eating disorder behaviours and diagnoses

Background Eating behaviours in childhood are considered as risk factors for eating disorder behaviours and diagnoses in adolescence. However, few longitudinal studies have examined this association. Aims We investigated associations between childhood eating behaviours during the first ten years of life and eating disorder behaviours (binge eating, purging, fasting and excessive exercise) and diagnoses (anorexia nervosa, binge eating disorder, purging disorder and bulimia nervosa) at 16 years. Method Data on 4760 participants from the Avon Longitudinal Study of Parents and Children were included. Longitudinal trajectories of parent-rated childhood eating behaviours (8 time points, 1.3-9 years) were derived by latent class growth analyses. Eating disorder diagnoses were derived from self-reported, parent-reported and objectively measured anthropometric data at age 16 years. We estimated associations between childhood eating behaviours and eating disorder behaviours and diagnoses, using multivariable logistic regression models. Results Childhood overeating was associated with increased risk of adolescent binge eating (risk difference, 7%; 95% CI 2 to 12) and binge eating disorder (risk difference, 1%; 95% CI 0.2 to 3). Persistent undereating was associated with higher anorexia nervosa risk in adolescent girls only (risk difference, 6%; 95% CI, 0 to 12). Persistent fussy eating was associated with greater anorexia nervosa risk (risk difference, 2%; 95% CI 0 to 4).Conclusions Our results suggest continuities of eating behaviours into eating disorders from early life to adolescence. It remains to be determined whether childhood eating behaviours are an early manifestation of a specific phenotype or whether the mechanisms underlying this continuity are more complex. Findings have the potential to inform preventative strategies for eating disorders

Associations between blood metabolic profile at 7 years old and eating disorders in adolescence: Findings from the avon longitudinal study of parents and children

Eating disorders are severe illnesses characterized by both psychiatric and metabolic factors. We explored the prospective role of metabolic risk in eating disorders in a UK cohort (n = 2929 participants), measuring 158 metabolic traits in non-fasting EDTA-plasma by nuclear magnetic resonance. We associated metabolic markers at 7 years (exposure) with risk for anorexia nervosa and binge-eating disorder (outcomes) at 14, 16, and 18 years using logistic regression adjusted for maternal education, child's sex, age, body mass index, and calorie intake at 7 years. Elevated very low-density lipoproteins, triglycerides, apolipoprotein-B/A, and monounsaturated fatty acids ratio were associated with lower odds of anorexia nervosa at age 18, while elevated high-density lipoproteins, docosahexaenoic acid and polyunsaturated fatty acids ratio, and fatty acid unsaturation were associated with higher risk for anorexia nervosa at 18 years. Elevated linoleic acid and n-6 fatty acid ratios were associated with lower odds of binge-eating disorder at 16 years, while elevated saturated fatty acid ratio was associated with higher odds of binge-eating disorder. Most associations had large confidence intervals and showed, for anorexia nervosa, different directions across time points. Overall, our results show some evidence for a role of metabolic factors in eating disorders development in adolescence

Genetic predisposition influences plasma lipids of participants on habitual diet, but not the response to reductions in dietary intake of saturated fatty acids

Objective: SNPs identified from genome wide association studies associate with lipid risk markers of cardiovascular disease. This study investigated whether these SNPs altered the plasma lipid response to diet in the ‘RISCK’ study cohort. Methods: Participants (n = 490) from a dietary intervention to lower saturated fat by replacement with carbohydrate or monounsaturated fat, were genotyped for 39 lipid-associated SNPs. The association of each individual SNP, and of the SNPs combined (using genetic predisposition scores), with plasma lipid concentrations was assessed at baseline, and on change in response to 24 weeks on diets. Results: The associations between SNPs and lipid concentrations were directionally consistent with previous findings. The genetic predisposition scores were associated with higher baseline concentrations of plasma total(P = 0.02) and LDL (P = 0.002) cholesterol, triglycerides (P = 0.001) and apolipoprotein B (P = 0.004), and with lower baseline concentrations of HDL cholesterol (P < 0.001) and apolipoprotein A-I (P < 0.001). None of the SNPs showed significant association with the reduction of plasma lipids in response to the dietary interventions and there was no evidence of diet-gene interactions. Conclusion: Results from this exploratory study have shown that increased genetic predisposition was associated with an unfavourable plasma lipid profile at baseline, but did not influence the improvement in lipid profiles by the low-saturated-fat diets

Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3

Objective: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m2" is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children. Methods: A GWAS of height-adjusted BMI (BMI[x]=weight/heightx), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed. Results: GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m3.1 change per allele G (0.19, 0.38), P=6 × 10-9). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m2 (0.15, 0.35), P=6 × 10-7)]. Results were replicated in an independent sample, the Generation R study. Conclusions: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits

Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE study

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of 6 correlated (Pearson's r range: |0.04-0.92|) RBC traits in up to 19 036 African Americans and 19 562 Hispanic/Latino participants of the Population Architecture using Genomics and Epidemiology consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11 000 SNPs flanking 13 previously identified association signals as well as 150 000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p &lt; 1.7 × 10 −4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p = 1.9 × 10 −7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. © 2018 Wiley Periodicals, Inc

Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics

Background: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations. © 2020 The Author(s)

Genetics of chronic kidney disease stages across ancestries: The PAGE study

Background: Chronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study. Methods: We assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity. Results: The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry. Conclusion: Our genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations. Copyright © 2019 Lin, Nadkarni, Tao, Graff, Fornage, Buyske, Matise, Highland, Wilkens, Carlson, Park, Setiawan, Ambite, Heiss, Boerwinkle, Lin, Morris, Loos, Kooperberg, North, Wassel and Franceschini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. Methods: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. Results: Four novel associations were identified (p < 5 × 10−9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. Conclusions/interpretation: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. Data availability: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics)

Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study

Background: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. Conclusions: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits

Gene × dietary pattern interactions in obesity: Analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GR