Effects of single genetic variants and polygenic obesity risk scores on disordered eating in adolescents – The HUNT study

Obese Asians are more susceptible to metabolic diseases than obese Caucasians of the same body mass index (BMI). We hypothesized that the genetic variants associated with obesity risk interact with the lifestyles of middle-aged and elderly adults, possibly allowing the development of personalized interventions based on genotype. We aimed to examine this hypothesis in a large city hospital-based cohort in Korea. The participants with cancers, thyroid diseases, chronic kidney disease, or brain-related diseases were excluded. The participants were divided into case and control according to their BMI: ≥25 kg/m2 (case; n = 17,545) and <25 kg/m2 (control; n = 36,283). The genetic variants that affected obesity risk were selected using a genome-wide association study, and the genetic variants that interacted with each other were identified by generalized multifactor dimensionality reduction analysis. The selected genetic variants were confirmed in the Ansan/Ansung cohort, and polygenetic risk scores (PRS)−nutrient interactions for obesity risk were determined. A high BMI was associated with a high-fat mass (odds ratio (OR) = 20.71) and a high skeletal muscle-mass index (OR = 3.38). A high BMI was positively related to metabolic syndrome and its components, including lipid profiles, whereas the initial menstruation age was inversely associated with a high BMI (OR = 0.78). The best model with 5-SNPs included SEC16B_rs543874, DNAJC27_rs713586, BDNF_rs6265, MC4R_rs6567160, and GIPR_rs1444988703. The high PRS with the 5-SNP model was positively associated with an obesity risk of 1.629 (1.475–1.798) after adjusting for the covariates. The 5-SNP model interacted with the initial menstruation age, fried foods, and plant-based diet for BMI risk. The participants with a high PRS also had a higher obesity risk when combined with early menarche, low plant-based diet, and a high fried-food intake than in participants with late menarche, high plant-based diet, and low fried-food intake. In conclusion, people with a high PRS and earlier menarche age are recommended to consume fewer fried foods and a more plant-based diet to decrease obesity risk. This result can be applied to personalized nutrition for preventing obesity.

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Intergenerational polygenic obesity risk throughout adolescence in a cross‐sectional study design: The HUNT study, Norway

Obesity ◽

10.1002/oby.23284 ◽

2021 ◽

Author(s):

Marit Næss ◽

Erik R. Sund ◽

Gunnhild Å. Vie ◽

Johan H. Bjørngaard ◽

Bjørn Olav Åsvold ◽

...

Keyword(s):

Study Design ◽

Cross Sectional Study ◽

Sectional Study ◽

Obesity Risk ◽

Cross Sectional ◽

Hunt Study ◽

Polygenic Obesity

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Has the time come to integrate genetic risk scores into clinical practice?

European Heart Journal ◽

10.1093/ehjci/ehaa946.3761 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

F.V Moniz Mendonca ◽

M.I Mendonca ◽

A Pereira ◽

J Monteiro ◽

J Sousa ◽

...

Keyword(s):

Risk Factors ◽

Clinical Practice ◽

Genetic Variants ◽

Genetic Risk ◽

Odds Ratio ◽

Risk Scores ◽

Cumulative Number ◽

Genetic Risk Scores ◽

Risk Alleles ◽

Cad Risk

Abstract Background The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice. Aim The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice. Methods A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated. Results A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p<0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002). Conclusion Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting. Funding Acknowledgement Type of funding source: None

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Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment

Brain ◽

10.1093/brain/awy277 ◽

2018 ◽

Vol 141 (12) ◽

pp. 3457-3471 ◽

Cited By ~ 7

Author(s):

Jiayuan Xu ◽

Qiaojun Li ◽

Wen Qin ◽

Mulin Jun Li ◽

Chuanjun Zhuo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Major Depressive Disorder ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Depressive Disorder ◽

Genetic Variants ◽

Amnestic Mild Cognitive Impairment ◽

Risk Scores ◽

Major Depressive

Abstract Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.

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Genetic variants associated with beta-cell function and insulin sensitivity potentially influence bile acid metabolites and gestational diabetes mellitus in a Chinese population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2021-002287 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002287

Author(s):

Qiulun Zhou ◽

Ying Wang ◽

Yuqin Gu ◽

Jing Li ◽

Hui Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Beta Cell ◽

Genetic Variants ◽

Cell Function ◽

Chinese Women ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Mediation Analyses

IntroductionTo investigate associations between genetic variants related to beta-cell (BC) dysfunction or insulin resistance (IR) in type 2 diabetes (T2D) and bile acids (BAs), as well as the risk of gestational diabetes mellitus (GDM).Research design and methodsWe organized a case-control study of 230 women with GDM and 217 without GDM nested in a large prospective cohort of 22 302 Chinese women in Tianjin, China. Two weighted genetic risk scores (GRSs), namely BC-GRS and IR-GRS, were established by combining 39 and 23 single nucleotide polymorphisms known to be associated with BC dysfunction and IR, respectively. Regression and mediation analyses were performed to evaluate the relationship of GRSs with BAs and GDM.ResultsWe found that the BC-GRS was inversely associated with taurodeoxycholic acid (TDCA) after adjustment for confounders (Beta (SE)=−0.177 (0.048); p=2.66×10−4). The BC-GRS was also associated with the risk of GDM (OR (95% CI): 1.40 (1.10 to 1.77); p=0.005), but not mediated by TDCA. Compared with individuals in the low tertile of BC-GRS, the OR for GDM was 2.25 (95% CI 1.26 to 4.01) in the high tertile. An interaction effect of IR-GRS with taurochenodeoxycholic acid (TCDCA) on the risk of GDM was evidenced (p=0.005). Women with high IR-GRS and low concentration of TCDCA had a markedly higher OR of 14.39 (95% CI 1.59 to 130.16; p=0.018), compared with those with low IR-GRS and high TCDCA.ConclusionsGenetic variants related to BC dysfunction and IR in T2D potentially influence BAs at early pregnancy and the development of GDM. The identification of both modifiable and non-modifiable risk factors may facilitate the identification of high-risk individuals to prevent GDM.

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Association of Established Blood Pressure Loci With 10‐Year Change in Blood Pressure and Their Ability to Predict Incident Hypertension

Journal of the American Heart Association ◽

10.1161/jaha.119.014513 ◽

2020 ◽

Vol 9 (16) ◽

Author(s):

Alaitz Poveda ◽

Naeimeh Atabaki‐Pasdar ◽

Shafqat Ahmad ◽

Göran Hallmans ◽

Frida Renström ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Genetic Variants ◽

Association Studies ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Swedish Population ◽

Long Term Changes ◽

Traditional Risk Factors

Background Genome‐wide association studies have identified >1000 genetic variants cross‐sectionally associated with blood pressure variation and prevalent hypertension. These discoveries might aid the early identification of subpopulations at risk of developing hypertension or provide targets for drug development, amongst other applications. The aim of the present study was to analyze the association of blood pressure‐associated variants with long‐term changes (10 years) in blood pressure and also to assess their ability to predict hypertension incidence compared with traditional risk variables in a Swedish population. Methods and Results We constructed 6 genetic risk scores (GRSs) by summing the dosage of the effect allele at each locus of genetic variants previously associated with blood pressure traits (systolic blood pressure GRS (GRS SBP ): 554 variants; diastolic blood pressure GRS (GRS DBP ): 481 variants; mean arterial pressure GRS (GRS MAP ): 20 variants; pulse pressure GRS (GRS PP ): 478 variants; hypertension GRS (GRS HTN ): 22 variants; combined GRS (GRS com b ): 1152 variants). Each GRS was longitudinally associated with its corresponding blood pressure trait, with estimated effects per GRS SD unit of 0.50 to 1.21 mm Hg for quantitative traits and odds ratios (ORs) of 1.10 to 1.35 for hypertension incidence traits. The GRS comb was also significantly associated with hypertension incidence defined according to European guidelines (OR, 1.22 per SD; 95% CI, 1.10‒1.35) but not US guidelines (OR, 1.11 per SD; 95% CI, 0.99‒1.25) while controlling for traditional risk factors. The addition of GRS comb to a model containing traditional risk factors only marginally improved discrimination (Δarea under the ROC curve = 0.001–0.002). Conclusions GRSs based on discovered blood pressure‐associated variants are associated with long‐term changes in blood pressure traits and hypertension incidence, but the inclusion of genetic factors in a model composed of conventional hypertension risk factors did not yield a material increase in predictive ability.

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GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

Pharmacogenomics ◽

10.2217/pgs-2019-0054 ◽

2019 ◽

Vol 20 (10) ◽

pp. 765-780 ◽

Cited By ~ 1

Author(s):

Diana Cruz ◽

Ricardo Pinto ◽

Margarida Freitas-Silva ◽

José Pedro Nunes ◽

Rui Medeiros

Keyword(s):

Atrial Fibrillation ◽

Genetic Variants ◽

Complex Traits ◽

Association Studies ◽

Cardioembolic Stroke ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

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Suicidal ideation in relation to disordered eating, body size and weight perception: a cross-sectional study of a Norwegian adolescent population: the HUNT Study

BMJ Open ◽

10.1136/bmjopen-2019-029809 ◽

2019 ◽

Vol 9 (7) ◽

pp. e029809 ◽

Cited By ~ 2

Author(s):

Farzaneh Saeedzadeh Sardahaee ◽

Turid Lingaas Holmen ◽

Nadia Micali ◽

Erik R Sund ◽

Ottar Bjerkeset ◽

...

Keyword(s):

Body Size ◽

Suicidal Ideation ◽

Disordered Eating ◽

Weight Perception ◽

Population Based ◽

Cross Sectional Study ◽

Cross Sectional ◽

Logistic Regression Models ◽

Norwegian Population ◽

Hunt Study

ObjectiveWe conducted a population-based study on a sample of more than 7000 adolescents where we examined the associations between suicidal ideation (SI) and disordered eating (DE) and its related traits.DesignCross-sectional.SettingsData were derived from two Norwegian population-based cohorts, the Young-HUNT1 (1995–1997) and Young-HUNT3 (2006–2008) from the county of Nord-Trøndelag, Norway.ParticipantsA total of 7268 adolescents (15–19 years) who had completed self-reported questionnaires including items on SI, DE, body size and weight perception were included.Primary outcome measuresORs for SI given DE, body size or weight perception. Analyses were performed in multivariate logistic regression models.ResultsThe prevalence of SI was 23.1% in total population. Both girls and boys who reported DE, evaluated their body size asnot‘about the same as others’ or were ‘unhappy about their weight’ had between twofold to fivefold increase in odds for SI; these incremental risks were observed independent of sex, age, body mass index and socioeconomic status. We observed higher odds for SI among boys.ConclusionsOur findings suggest a clear association between SI and DE and its associated traits, in both genders but especially in males. Special attention should be paid on early detection of DE traits among adolescents.

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Metabolomic Links Between Sweetened Beverage Intake and Obesity (OR31-05-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz037.or31-05-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Chao-Qiang Lai ◽

Reiko Ichikawa ◽

Bingjie Zhou ◽

Laurence Parnell ◽

Sabrina Noel ◽

...

Keyword(s):

Genetic Variants ◽

Metabolic Pathways ◽

Enrichment Analysis ◽

Health Study ◽

Pathway Enrichment Analysis ◽

Linear Regression Models ◽

Obesity Risk ◽

Pathway Enrichment ◽

Sweetened Beverage ◽

Increased Risk

Abstract Objectives Sweetened beverage (SB) consumption is highly associated with obesity, but the mechanism underlying this correlation is not understood. Our objective was to examine metabolomic links between SB intake and obesity to understand metabolic mechanisms. Methods We examined the association of plasma metabolomic profiles with SB intake and obesity risk in 782 participants, aged 45–75y, in the Boston Puerto Rican Health Study (BPRHS) using linear regression models, controlling for potential confounding factors. Based on identified metabolites, we conducted pathway enrichment analysis to identify potential metabolic pathways that link SB intake and obesity risk. Genetic variants in identified metabolic pathways were examined for their interaction with SB intake on metabolites of interest and obesity. Interactions between SB and genotypes on obesity were evaluated for replication in the Framingham Heart Study (FHS). Results In BPRHS, SB intake was highly correlated with BMI (β = 0.455, P < 0.05). Among 526 measurable metabolites, 109 metabolites showed significant correlation with SB intake and 170 metabolites with BMI (P < 0.05); and 43 were correlated with both SB intake and BMI. Pathway enrichment analysis identified two metabolic pathways: phosphatidylethanolamine (PE) and lysophospholipid pathways linking SB intake and obesity, after correction for multiple testing. Focusing on the PE pathway, we identified 12 SNPs in nine genes that were significantly associated with BMI. At least four genetic variants showed suggestive interaction with SB intake on obesity risk and obesity-associated metabolites. In particular, CC carriers of rs4646360 in the PEMT (Phosphatidylethanolamine N-Methyltransferase) gene had increased risk of obesity when consuming SB. We replicated this finding in the FHS study. Conclusions We identified two key metabolic pathways linking SB intake to obesity, revealing potential mechanisms by which SB intake increases the risk of obesity. The interaction between genetic variants in the identified pathway and SB intake on obesity and obesity-associated metabolites further supports the mechanism. Funding Sources This work was funded by the US Department of Agriculture, under agreement no. 8050-51,000-098-00D, and NIH grants P01 AG023394, P50 HL105185, and R01 AG027087.

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Polygenic Score for Body Mass Index Is Associated with Disordered Eating in a General Population Cohort

Journal of Clinical Medicine ◽

10.3390/jcm9041187 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1187 ◽

Cited By ~ 6

Author(s):

Mohamed Abdulkadir ◽

Moritz Herle ◽

Bianca L. De Stavola ◽

Christopher Hübel ◽

Diana L. Santos Ferreira ◽

...

Keyword(s):

Body Mass Index ◽

Binge Eating ◽

Body Dissatisfaction ◽

Disordered Eating ◽

Body Mass ◽

Genetic Variants ◽

Emotional Eating ◽

Mediation Analyses ◽

Parents And Children ◽

Polygenic Scores

Background: Disordered eating (DE) is common and is associated with body mass index (BMI). We investigated whether genetic variants for BMI were associated with DE. Methods: BMI polygenic scores (PGS) were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8654) and their association with DE tested. Data on DE behaviors (e.g., binge eating and compensatory behaviors) were collected at ages 14, 16, 18 years, and DE cognitions (e.g., body dissatisfaction) at 14 years. Mediation analyses determined whether BMI mediated the association between the BMI-PGS and DE. Results: The BMI-PGS was positively associated with fasting (OR = 1.42, 95% CI = 1.25, 1.61), binge eating (OR = 1.28, 95% CI = 1.12, 1.46), purging (OR = 1.20, 95% CI = 1.02, 1.42), body dissatisfaction (Beta = 0.99, 95% CI = 0.77, 1.22), restrained eating (Beta = 0.14, 95% CI = 0.10, 1.17), emotional eating (Beta = 0.21, 95% CI = 0.052, 0.38), and negatively associated with thin ideal internalization (Beta = −0.15, 95% CI = −0.23, −0.07) and external eating (Beta = −0.19, 95% CI = −0.30, −0.09). These associations were mainly mediated by BMI. Conclusions: Genetic variants associated with BMI are also associated with DE. This association was mediated through BMI suggesting that weight potentially sits on the pathway from genetic liability to DE.

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