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Background and AimsCardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits.Methods and ResultsWe conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high-density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N=356,574–456,823). Multiple loci reached genome-wide levels of significance (N=145-333) for each trait, but only four loci (in/nearVEGFA, GRB14-COBLL1, KLF14, andRGS19-OPRL1)were associated with risk across all seven traits (P−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses.GRB14-COBLL1showed the most consistent replication, revealing nominally significant associations (PConclusionsOur analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.

RationaleInflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health.ObjectivesInvestigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in adults of diverse races/ethnicities from general population cohorts.MethodsComplementary study designs: (1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1and FVC measures in the National Heart, Lung, and Blood Institute Pooled Cohorts Study, and (2) two-sample Mendelian Randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters.Measurements and Main ResultsThe longitudinal study found that higher omega-3 fatty acid concentrations were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for docosahexaenoic acid (DHA). One standard deviation higher DHA was associated with an attenuation of 1.8 mL/year for FEV1(95% confidence interval [CI] 1.3–2.2) and 2.4 mL/year for FVC (95% CI 1.9–3.0). One standard deviation higher DHA was also associated with a 9% lower incidence of spirometry-defined airway obstruction (95% CI 0.86–0.97). DHA associations persisted across sexes, smoking histories, and Black, white and Hispanic participants, with the largest magnitude associations in former smokers and Hispanics. The MR study showed positive associations of genetically predicted omega-3 fatty acids with FEV1and FVC, with statistically significant findings across multiple MR methods.ConclusionsThe longitudinal and MR studies provide evidence supporting beneficial effects of higher circulating omega-3 fatty acids, especially DHA, on lung health.

Background and aimsThe DASH diet conveys protection against type 2 diabetes mellitus (T2D) Via plant-based and non-plant-based recommendations. Research has not identified which glucose homeostasis pathways are improved. We examined associations between adherence to a DASH diet and six glucose homeostasis traits, probing whether associations could be attributed to the plant-based (DASH-P) and/or non-plant based (DASH-NP) components.Methods and resultsWe included data from 295 adults without T2D (age 59.3±9.00 years; 63.46% non-Hispanic White and 36.54% African American, self-reported race ancestry) participating in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). An oral glucose tolerance test (OGTT) yielded fasting plasma glucose, insulin, C-peptide, and insulin secretion, sensitivity, and disposition index. Habitual dietary intake was assessed by food frequency questionnaire (FFQ). Associations between DASH components and glucose homeostasis traits were examined, controlling for demographics, body mass index (BMI), physical activity, and energy intake. For significant associations, the models were repeated with scores for DASH-P and DASH-NP as predictors in the same model. DASH and DASH-P scores were inversely associated with fasting plasma glucose (DASH:β=-0.036±0.012,P=0.005; DASH-P: β=-0.04±0.017,P=0.002), and positively associated with insulin sensitivity (DASH:β=0.022±0.012,P=0.042; DASH-P:=0.036±0.015,P=0.014). The DASH score was also associated with disposition index (β=0.026±0.013,P=0.038), but this association did not reach significance with DASH-P (β=0.035±0.018,P=0.051). No associations were observed with DASH-NP score (all P>0.05).ConclusionsDASH diet is associated with improvement in specific glucose homeostasis traits, likely arising from increased plant-based foods. Such research may help tailor future dietary advice to specific metabolic risk, and to food groups most effective at improving these.

Aim To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). Materials and methods The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. Results After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. Conclusions The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.

BackgroundVitamin D inadequacy affects almost 50% of adults in the United States and is associated with numerous adverse health effects. Vitamin D concentration [25(OH)D] is a complex trait with genetic and environmental predictors that work in tandem to influence 25(OH)D and may determine how much vitamin D intake is required to reach an optimal 25(OH)D concentration. To date, there has been little investigation into how genetics and environment interact to affect 25(OH)D.ObjectiveInteractions between continuous measures of a polygenic score (PGS) and vitamin D intake (PGS*intake) or available ultra-violet (UV) radiation (PGS*UV) were evaluated separately in individuals of African or European ancestry.MethodsMega-analyses were performed using three independent cohorts (N=9,668; African ancestry n=1,099; European ancestry n=8,569). Interaction terms and joint effects (main and interaction terms) were tested using one-degree of freedom (DF) and 2-DF models, respectively. All models controlled for age, sex, body mass index (BMI), cohort, and dietary intake/available UV. Additionally, in participants achieving Institute of Medicine (IOM) vitamin D intake recommendations, 25(OH)D was evaluated by level of genetic risk of 25(OH)D deficiency.ResultsThe 2-DF PGS*intake, 1-DF PGS*UV and 2-DF PGS*UV results were statistically significant in participants of European ancestry (p=3.3×10−18, 2.1×10−2, and 2.4×10−19, respectively), but not in those of African ancestry. In European-ancestry participants who reached IOM vitamin D intake guidelines, the percent of participants achieving adequate 25(OH)D (>20ng/ml) increased as genetic risk decreased (72% vs 89% in the highest vs lowest risk categories; p=0.018).ConclusionsAvailable UV radiation and vitamin D intake interact with genetics to influence 25(OH)D. Individuals with higher genetic risk of deficiency may require more vitamin D exposure to maintain optimal 25(OH)D concentrations. Overall, the results showcase the importance of incorporating both environmental and genetic factors into analyses, as well as the potential for gene-environment interactions to inform personalized dosing of vitamin D.Sources of SupportARICThe Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions.Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E. Boerwinkle).MESAMESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491.The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226.Funding support for the Vitamin D dataset was provided by grant HL096875WHIThe WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI.WHI PAGE is funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) network (Grant Number U01 HG004790). Assistance with phenotype harmonization, SNP selection, data cleaning, meta-analyses, data management and dissemination, and general study coordination, was provided by the PAGE Coordinating Center (U01HG004801-01).Funding support for WHI GARNET was provided through the NHGRI Genomics and Randomized Trials Network (GARNET) (Grant Number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004424). The datasets used for the analyses described in this manuscript were obtained from dbGaP athttp://www.ncbi.nlm.nih.gov/sites/entrez?db=gapthrough dbGa Paccession phs000200.v11.p3.Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278.OtherKEH was supported by an NLM training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). Computational resources were supported by a core grant to the Center for Demography and Ecology at the University of Wisconsin-Madison (P2C HD047873).JM was supported by the Department of Ophthalmology and Visual Sciences, and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences from the Research to Prevent Blindness, and by National Institutes of Health, National Eye Institute grants R01 EY016686, R01 EY025292.

Introduction In observational studies, the association between the Dietary Approaches to Stop Hypertension (DASH) diet and incident heart failure has been inconsistent. It was hypothesized that higher DASH diet concordance has a protective effect on heart failure in a multi-ethnic cohort. Methods The Multi-Ethnic Study of Atherosclerosis cohort includes men and women of multiple ethnicities who were aged 45–84 years and free of clinical cardiovascular disease at baseline. Participants were recruited between 2000 and 2002 from six U.S. communities and followed for incident cardiovascular health events through 2015 for the purpose of this data set. Diet was measured using food-frequency questionnaires. Cox proportional hazards analysis was used to investigate the associations of the DASH diet concordance with incident heart failure in 2017–2018. Results During a median 13 years of follow-up, 179 of 4,478 participants developed heart failure, corresponding to a rate of 3.4 per 1,000 person years. Heart failure incidence rates did not vary significantly by DASH quintile for the population as a whole. In participants younger than 75 years, highest DASH concordance was associated with a lower risk of incident heart failure compared with those in the lowest quintile (hazard ratio=0.4, 95% CI=0.2, 0.9 vs all participants hazard ratio=1.0, 95% CI=0.2, 0.9) after adjusting for demographics, energy consumption, and known cardiovascular confounders. Conclusions This study supports the hypothesis that DASH is beneficial in heart failure prevention within the individuals aged less than 75 years subgroup, an idea that to date was substantiated only by much smaller studies or in less diverse patient populations.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk., Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p, Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.

PURPOSE OF REVIEW: Current feeding advice to prevent pediatric obesity focusses on caregiver feeding behaviors. This review integrates newer data showing that child appetitive traits also have a genetic component. RECENT FINDINGS: Caregiver feeding behaviors robustly correlate with child eating behaviors; however there is also a strong heritable component. SUMMARY: The satiety cascade delineates the biological drive underlying hunger, satiation and satiety. Innate individual differences exist for the components of the satiety cascade, which may explain the heritability of child eating behaviors. However, given the correlation of caregiver feeding behaviors with child eating behaviors any etiological model should include both genetic/biological components and environmental. Integrating the biological etiology of child eating behaviors into the current environmental model has implications for tailoring feeding advice which needs to move from a “one size fits all” approach, to one that is tailored to individual differences in children’s biological drives to appetite.

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

ContextVitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D concentrations are influenced by genetic factors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors contributing to differences in 25(OH)D levels has been discovered.ObjectiveTherefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of morbidity and mortality from deficient 25(OH)D.DesignUsing PRSice and weights from published African- and European-ancestry GWAS summary statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of genetic factors.Patients or Other ParticipantsParticipants (European ancestry n=9,569, African ancestry n=2,761) came from three cohort studies.Main Outcome Measure(s)Blood concentrations of 25(OH)D.ResultsThe PGS for African ancestry was derived using all input SNPs (a p-value cut-off of 1.0) and had an R2of 0.3%; for European ancestry, the optimal PGS used a p-value cut-off of 3.5×10−4in the target/tuning dataset and had an R2of 1.0% in the validation cohort. Those with highest genetic risk had 25(OH)D that was 2.8-3.0 ng/ml lower than those with lowest genetic risk (p=0.0463 to 3.2×10−13), requiring an additional 467 to 500 IU of vitamin D intake to maintain equivalent 25(OH)D.ConclusionsPGSs are a powerful predictive tool that could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of 25(OH)D inadequacy.

INTRODUCTION: In 2010, the American Heart Association initiated Life’s Simple 7 with the goal of significantly improving cardiovascular health by the year 2020. The association of Life’s Simple 7 with risk of peripheral artery disease has not been thoroughly explored. METHODS: Racially diverse individuals from the Multi-Ethnic Study of Atherosclerosis (2000–2012) were followed for incident peripheral artery disease (ankle brachial index ≤0.90) and decline in ankle brachial index (≥0.15) over approximately 10 years of follow-up. Cox and logistic regression were used to assess associations of individual Life’s Simple 7 components (score 0–2) and overall Life’s Simple 7 score (score 0–14) with incident peripheral artery disease and ankle brachial index decline, respectively, adjusted for age, sex, race/ethnicity, education, and income. Analyses were performed in 2016–2018. RESULTS: Of 5,529 participants, 251 (4.5%) developed incident peripheral artery disease; 419 (9.8%) of 4,267 participants experienced a decline in ankle brachial index. Each point higher for the overall Life’s Simple 7 score was associated with a 17% lower rate of incident peripheral artery disease (hazard ratio=0.83, 95% CI=0.78, 0.88, p

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

BACKGROUND AND PURPOSE: Dietary sodium reduction with concurrent increase in potassium intake is a current public health priority to reduce risk of cardiovascular events. This study explored associations between the spot urine sodium-to-potassium ratio and cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort. METHODS: The MESA is a prospective cohort study of 6,814 adults from 4 ethnic groups (European-, Asian-, African- and Hispanic-American) with a mean age of 62 (+/−10.2) years and an average of 11.7 (+/−2.2) years of follow-up. Participants were free of clinical cardiovascular disease at baseline. Spot urine sodium and potassium excretion, as a marker of dietary intake, was collected at baseline. The impact of urinary sodium-to-potassium ratio on adjudicated cardiovascular events was assessed using Cox proportional hazards models. RESULTS: Only 39% of MESA participants had a urinary sodium-to-potassium ratio ≤1 and these participants experienced only 74 of the 236 strokes. A sodium-to-potassium ratio >1 was associated with a hazard ratio of 1.47 (95% Confidence Interval: 1.07 to 2.00) for risk of stroke, adjusting for age, sex, race, cardiovascular risk factors, socio-demographic characteristics, body size, and kidney function. CONCLUSION: The spot urine sodium-to-potassium ratio (measurable in routine care) is associated with stroke. A urine sodium-to-potassium ratio of ≤1, may be related to a clinically relevant reduction in stroke risk and is a feasible target for health interventions.

H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. I.K. was supported by the EU PhenoMeNal project (Horizon 2020, grant no. 654241) and the UK Dementia Research Institute, which is supported by the MRC, the Alzheimer’s Society and Alzheimer’s Research UK. S. Thériault was supported by the Canadian Institutes of Health Research and Université Laval (Quebec City, Canada). L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Vaduz, Liechtenstein. D.C. holds a McMaster University Department of Medicine Mid-Career Research Award. M.B. is supported by NIH grant R01-DK062370. P.v.d.H. was supported by ICIN-NHI and Marie Skłodowska-Curie GF (call: H2020-MSCA-IF-2014; Project ID: 661395). C.H. was supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. N.V. was supported by Marie Skłodowska-Curie GF (grant no. 661395) and ICIN-NHI. Q.L. is partially supported by the National Natural Sciences Foundation of China (No. 81873909), Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01) and ZJLab. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1) and Health Data Research (HDR) UK. P.E. is supported by a UK Dementia Research Institute (DRI) professorship, UK DRI at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology; LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders; grant no. 695313), ERANID (Understanding the interplay between cultural, biological and subjective factors in drug use pathways; PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics; MR/N027558/1), the FP7 projects IMAGEMEND (grant no. 602450; IMAging GEnetics for MENtal Disorders) and MATRICS (grant no. 603016), the Innovative Medicine Initiative Project EU-AIMS (grant. no115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; and Forschungsnetz AERIAL 01EE1406A and 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2 and SFB 940/2), the Medical Research Foundation and Medical Research Council (MR/R00465X/1), the Human Brain Project (HBP SGA 2). Further support was provided by grants from ANR (project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1); and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence.

PURPOSE OF REVIEW: This narrative review describes the evidence for both genetic and environmental influences on child appetitive traits, and suggests ways of thinking about how these interact and correlate to influence how a child eats. RECENT FINDINGS: Emerging evidence from social network analysis, and from longitudinal studies questioning the direction of association between parent feeding behaviors and child obesity risk, suggest that children’s genes may shape the environmental risk for obesity that they are exposed to. SUMMARY: There is strong evidence that child appetitive traits are both heritable, and shaped by the environment. Instead of thinking about how genetic and environmental factors operate independently on each appetitive trait, research needs to expand the current paradigm to examine how genes and environments interact and shape each other.

BackgroundTwin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.MethodMultivariate familial models were run on data from 1265 individuals aged 6–18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice–delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).ResultsSignificant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41–0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80–87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.ConclusionsThe aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Objective To describe the utility of twin studies for attention-deficit/hyperactivity disorder (ADHD) research and demonstrate their potential for the identification of alternative phenotypes suitable for genomewide association, developmental risk assessment, treatment response, and intervention targets. Method Brief descriptions of the classic twin study and genetic association study methods are provided, with illustrative findings from ADHD research. Biometrical genetics refers to the statistical modeling of data gathered from one or more group of known biological relation; it was apparently coined by Francis Galton in the 1860s and led to the "Biometrical School" at the University of London. Twin studies use genetic correlations between pairs of relatives, derived using this theoretical framework, to parse the individual differences in a trait into latent (unmeasured) genetic and environmental influences. This method enables the estimation of heritability, i.e., the percentage of variance due to genetic influences. It is usually implemented with a method called structural equation modeling , which is a statistical technique for fitting models to data, typically using maximum likelihood estimation. Genetic association studies aim to identify those genetic variants that account for the heritability estimated in twin studies. Measurements other than those used for the clinical diagnosis of the disorder are popular phenotype choices in current ADHD research. It is argued that twin studies have great potential to refine phenotypes relevant to ADHD. Results Prior studies have consistently found that the majority of the variance in ADHD symptoms is due to genetic factors. To date, genomewide association studies of ADHD have not identified replicable associations that account for the heritable variation. Possibly, the application of genomewide association studies to these alternative phenotypic measurements will assist in identifying the pathways from genetic variants to ADHD. Conclusion Power to detect associations should be improved by the study of highly heritable endophenotypes for ADHD and by reducing the number of phenotypes to be considered. Therefore, twin studies are an important research tool in the development of endophenotypes, defined as alternative, more highly heritable traits that act at earlier stages of the pathway from genes to behavior. Although genetic variation in liability to ADHD is likely polygenic, the proposed approach should help to identify improved alternative measurements for genetic association studies.

Previous studies have documented the primarily genetic aetiology for the stronger phenotypic covariance between reading disability and ADHD inattention symptoms, compared to hyperactivity-impulsivity symptoms. In this study, we examined to what extent this covariation could be attributed to "generalist genes" shared with general cognitive ability or to "specialist" genes which may specifically underlie processes linking inattention symptoms and reading difficulties. We used multivariate structural equation modeling on IQ, parent and teacher ADHD ratings and parent ratings on reading difficulties from a general population sample of 1312 twins aged 7.9-10.9 years. The covariance between reading difficulties and ADHD inattention symptoms was largely driven by genetic (45%) and child-specific environment (21%) factors not shared with IQ and hyperactivity-impulsivity; only 11% of the covariance was due to genetic effects common with IQ. Aetiological influences shared among all phenotypes explained 47% of the variance in reading difficulties. The current study, using a general population sample, extends previous findings by showing, first, that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genes contributing to general cognitive ability and, second, that child-specific environment factors, independent from IQ, also contribute to the covariation between reading difficulties and inattention symptoms.

BackgroundAttention deficit hyperactivity disorder (ADHD) shows a strong phenotypic and genetic association with reaction time (RT) variability, considered to reflect lapses in attention. Yet we know little about whether this aetiological pathway is shared with other affected cognitive processes in ADHD, such as lower IQs or the generally slower responses (mean RTs). We aimed to address the question of whether a shared set of genes exist that influence RT variability, mean RT, IQ and ADHD symptom scores, or whether there is evidence of separate aetiological pathways.MethodMultivariate structural equation modelling on cognitive tasks data (providing RT data), IQ and ADHD ratings by parents and teachers collected on general population sample of 1314 twins, at ages 7–10 years.ResultsMultivariate structural equation models indicated that the shared genetic influences underlying both ADHD symptom scores and RT variability are also shared with those underlying mean RT, with both types of RT data largely indexing the same underlying liability. By contrast, the shared genetic influences on ADHD symptom scores and RT variability (or mean RT) are largely independent of the genetic influences that ADHD symptom scores share with IQ.ConclusionsThe finding of unique aetiological pathways between IQ and RT data, but shared components between mean RT, RT variability and ADHD symptom scores, illustrates key influences in the genetic architecture of the cognitive and energetic processes that underlie the behavioural symptoms of ADHD. In addition, the multivariate genetic model fitting findings provide valuable information for future molecular genetic analyses.

It is well known that there are strong genetic influences on attention-deficit hyperactivity disorder (ADHD), with genetic association studies providing good evidence for the involvement of the dopamine neurotransmitter system in its aetiology. Developmental origins of ADHD represent an interesting area of research to understand the genetics that underlie early appearing individual differences. However, understanding the molecular basis of ADHD requires accurate, unbiased, heritable measures that can be used for molecular genetic association analyses. We take two approaches to examine the genetics of ADHD behaviours in infancy. Using quantitative genetic techniques, we explore the relationship between objective measures of activity level (AL) in both home and laboratory environments as well as with parent ratings of ADHD symptoms in a population sample of 2-year-old twins. Molecular association analyses of these measures examine candidate genes previously associated with ADHD. We find that ADHD symptoms, AL in the home and AL in the lab represent heritable phenotypes in 2-year-old infants. AL measured in the home has a strong genetic correlation with symptoms of ADHD, whereas AL in the lab correlates only modestly with the same ADHD measure. Genetic correlations suggest that AL in the home is more comparable than AL in the lab to ADHD behaviour and support the separation of all three for molecular analyses. There was modest evidence for association between DAT1, NET1 and ADHD symptom scores, as well as between DAT1 and AL in the lab.

Motion sensor devices such as actigraphs are increasingly used in studies that seek to obtain an objective assessment of activity level. They have many advantages, and are useful additions to research in fields such as sleep assessment, drug efficacy, behavior genetics, and obesity. However, questions still remain over the reliability of data collected using actigraphic assessment. We aimed to apply generalizability theory to actigraph data collected on a large, general-population sample in middle childhood, during 8 cognitive tasks across two body loci, and to examine reliability coefficients on actigraph data aggregated across different numbers of tasks and different numbers of attachment loci. Our analyses show that aggregation greatly increases actigraph data reliability, with reliability coefficients on data collected at one body locus during 1 task (.29) being much lower than that aggregated across data collected on two body loci and during 8 tasks (.66). Further increases in reliability coefficients by aggregating across four loci and 12 tasks were estimated to be modest in prospective analyses, indicating an optimum trade-off between data collection and reliability estimates. We also examined possible instrumental effects on actigraph data and found these to be nonsignificant, further supporting the reliability and validity of actigraph data as a method of activity level assessment.

Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs.Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III).Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ.Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.

We aimed to investigate the relationship between dietary saturated fat on fasting triglyceride (TG) and cholesterol levels, and any mediation of this relationship by dietary carbohydrate intake. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study ( n = 1036, mean age ± SD = 49 ± 16 y) were included. Mixed linear models were run with saturated fat as a predictor variable and fasting TG, very low density lipoprotein cholesterol (VLDL-C), low density cholesterol (LDL-C) and high density cholesterol (HDL-C) as separate outcome variables. Subsequent models were run which included dietary carbohydrate as a predictor variable, and an interaction term between saturated fat and carbohydrate. All models controlled for age, sex, BMI, blood pressure and dietary covariates. In models that included only saturated fat as a predictor, saturated fat did not show significant associations with fasting lipids. When carbohydrate intake and an interaction term between carbohydrates and saturated fat intake was included, carbohydrate intake did not associate with lipids, but there was an inverse relationship between saturated fat intake and VLDL-C ( P = 0.01) with a significant interaction ( P = 0.01) between saturated fat and carbohydrate with regard to fasting VLDL-C concentrations. Similar results were observed for fasting TG levels. We conclude that, when controlling for carbohydrate intake, higher saturated fat was associated with lower VLDL-C and TGs. This was not the case at higher intakes of carbohydrate. This has important implications for dietary advice aimed at reducing TG and VLDL-C levels.

Attention deficit hyperactivity disorder and oppositional behaviours frequently co-occur, We aimed to study the etiology of this overlap in a general population-based twin sample, assessing the symptom domains of hyperactivity-impulsivity and inattentiveness separately for their overlap with oppositionality. We further aimed to investigate whether rater bias may contribute to the overlap in previous data which used one rater only. Using parent and teacher ratings on hyperactivity-impulsivity, inattentiveness and oppositionality, and actigraph measurements of activity level, for 668 7-9-year-old twin pairs, oppositionality showed a higher overlap with hyperactivity-impulsivity (r = 0.95) than with inattentiveness (r = 0.52) and all etiological influences on hyperactivity-impulsivity were shared with those on oppositionality, indicated by a genetic correlation of 0.95 and a child-specific environmental correlation of 0.94. Actigraph data did not show an overlap with ratings of oppositionality. In middle childhood, symptoms of hyperactivity-impulsivity and oppositional behaviour may represent the same underlying liability, whereas the inattentive domain is more distinct.

Focusing on symptoms of attention deficit hyperactivity disorder (ADHD) in a sample obtained from the general population, we aimed to investigate the effects of incentives and event rate on reaction time (RT) performance and response inhibition. We assessed 1156 children, at a mean age of 8 years, on their performance on an inhibition task and a RT task under different experimental conditions that manipulated event rate and incentives. Children with high ADHD (ADHD-H) symptoms showed cognitive performance deficits only under some of the experimental conditions compared to a control group. The fast-incentive condition of the RT task succeeded in normalizing the RT variability, as well as the slow overall speed, in the ADHD-H group. Analyses of ADHD symptom scores as a quantitative trait in the total sample were overall consistent with these findings. The findings suggest that at least some cognitive performance deficits in children with high ADHD symptoms do not reflect stable cognitive deficits. The degree to which cognitive impairments in ADHD can be modulated by energetic or motivational factors has important implications for clinical and educational interventions. (JINS, 2009, 15, 570–579.)

Despite the high heritability of children's activity level, which forms part of the core symptom domain of hyperactivity-impulsivity within attention deficit hyperactivity disorder (ADHD), there has only been a limited success with identifying candidate genes involved in its etiology. This may reflect a lack of understanding about the different measures used to define activity level across studies. We aimed to study the genetic and environmental etiology across three measures of activity level: parent and teacher ratings of hyperactivity-impulsivity and actigraph measurements, within a population-based sample of 463 7-9 year old twin pairs. We further examined ways in which the three measures could be combined for future molecular studies. Phenotypic correlations across measures were modest, but a common underlying phenotypic factor was highly heritable (92%); as was a simple aggregation of all three measurements (77%). This suggests that distilling what is common to all three measures may be a good method for generating a quantitative trait suitable for molecular studies of activity level in children. The high heritabilities found are encouraging in this respect.

Contains fulltext : 89304.pdf (Publisher’s version ) (Open Access) CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots or separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations. OBJECTIVES: To determine, by using a multivariate familial factor analysis approach, whether 1 or more familial factors underlie the slow and variable reaction times, impaired response inhibition, and choice impulsivity associated with ADHD. DESIGN: An ADHD and control sibling-pair design. SETTING: Belgium, Germany, Ireland, Israel, Spain, Switzerland, and the United Kingdom. PARTICIPANTS: A total of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with combined-subtype ADHD), and 345 control participants. MAIN OUTCOME MEASURES: Performance on a 4-choice reaction time task, a go/no-go inhibition task, and a choice-delay task. RESULTS: The final model consisted of 2 familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98% to 100% of the familial influences on mean reaction time and reaction time variability. The second, smaller factor, reflecting 13% of the familial variance of ADHD, captured 62% to 82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model because of poor fit. CONCLUSIONS: The findings suggest the existence of 2 familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the 2 cognitive impairments is consistent with recent theoretical models--a developmental model and an arousal-attention model--of 2 separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally sensitive interventions. 01 november 2010