Mariaelisa Graff

Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Working to eat: Vulnerability, food insecurity, and obesity among migrant and seasonal farmworker families

BACKGROUND Food insecurity and obesity have potential health consequences for migrant and seasonal farm workers (MSFW). METHODS Thirty-six Latino MSFW working in eastern North Carolina whose children attended Migrant Head Start completed interviews, focus groups and home visits. Content analysis, nutrient analysis, and non-parametric statistical analysis produced results. RESULTS MSFW (63.8%) families were food insecure; of those, 34.7% experienced hunger. 32% of pre-school children were food insecure. Food secure families spent more money on food. Obesity was prevalent in adults and children but the relationship to food insecurity remains unclear. Strategies to reduce risk of foods insecurity were employed by MSFW, but employer and community assistance is needed to reduce their risk. CONCLUSIONS Food insecurity is rooted in the cultural lifestyle of farmwork, poverty, and dependency. MSFW obesity and food insecurity require further study to determine the relationship with migration and working conditions. Networking and social support are important for MSFW families to improve food security. Policies and community/workplace interventions could reduce risk of food insecurity and improve the health of workers.

Genetic epidemiology of bmi and body mass change from adolescence to young adulthood

The complex interplay between genes and environment affecting body mass gain over lifecycle periods of risk is not well understood. We use longitudinal sibling cohort data to examine the role of shared household environment, additive genetic, and shared genetic effects on BMI and BMI change. In the National Longitudinal Study of Adolescent Health, siblings and twin pairs sharing households for ≥10 years as adolescents (N = 5,524; mean = 16.5 ± 1.7 years) were followed into young adulthood (N = 4,368; mean = 22.4 ± 1.8 years). Using a variance component approach, we quantified genetic and household effects on BMI in siblings and nonsiblings sharing household environments over time. Adjusting for race, age, sex, and age‐by‐sex interaction, we detected a heritability of 0.43 ± 0.05 for BMI change. Significant household effects were noted during the young adulthood period only (0.11 ± 0.06). We find evidence for shared genetic effects between BMI and BMI change during adolescence (genetic correlation (ρG) = 0.61 ± 0.03) and young adulthood (ρG = 0.23 ± 0.06). Our findings support a complex etiology of BMI and BMI change.

The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

Sex and race differences in the prevalence of fatty liver disease as measured by computed tomography liver attenuation in European American and African American participants of the NHLBI family heart study.

Background and aims Liver attenuation (LA) [Hounsfield Units (HU)] by computed tomography is a validated quantitative measure that is inversely related to liver fat burden. We examined race and sex differences on the distribution of LA [one of the first stages of fatty liver disease (FLD)] and the predictors of these mean differences in European American (EA) and African American (AA) participants of the Family Heart Study. Materials and methods A total of 1242 (1064 EA, 178 AA) and 1477 (1150 EA, 327 AA) men and women, respectively, underwent computed tomography examination from which LA and abdominal adipose volume were measured. LA (adjusted for phantom and field center) was the dependent variable in linear mixed models (to control for family relatedness) that tested for mean differences by race and by sex. Independent explanatory variables included age, BMI, visceral adipose tissue volume (VAT), subcutaneous adipose tissue volume, alcohol consumption, triglyceride, HDL-cholesterol, and insulin resistance. Results Mean LA varied significantly by sex, [(men) 57.76±10.03 HU and (women) 60.03±10.91 HU, P=0.0002], but not by race. Higher LA was associated with older age, whereas higher values of VAT, triglycerides, and insulin resistance were associated with lower LA in men and women. In contrast, alcohol consumption and BMI were associated with lower LA only among men. In analyses stratified by race, LA was associated with alcohol consumption, VAT, and insulin resistance in both EA and AA and with age, BMI, and HDL-cholesterol in EA participants only. Conclusions Our study findings confirm that there are important sex differences and race by sex interaction effects on the distribution of LA, the prevalence of FLD, and on the influence of metabolic risk factors on LA and FLD.

A powerful statistical framework for generalization testing in GWAS, with application to the HCHS/SOL

In genome‐wide association studies (GWAS), “generalization” is the replication of genotype‐phenotype association in a population with different ancestry than the population in which it was first identified. Current practices for declaring generalizations rely on testing associations while controlling the family‐wise error rate (FWER) in the discovery study, then separately controlling error measures in the follow‐up study. This approach does not guarantee control over the FWER or false discovery rate (FDR) of the generalization null hypotheses. It also fails to leverage the two‐stage design to increase power for detecting generalized associations. We provide a formal statistical framework for quantifying the evidence of generalization that accounts for the (in)consistency between the directions of associations in the discovery and follow‐up studies. We develop the directional generalization FWER (FWERg) and FDR (FDRg) controlling r‐values, which are used to declare associations as generalized. This framework extends to generalization testing when applied to a published list of Single Nucleotide Polymorphism‐(SNP)‐trait associations. Our methods control FWERg or FDRg under various SNP selection rules based on P‐values in the discovery study. We find that it is often beneficial to use a more lenient P‐value threshold than the genome‐wide significance threshold. In a GWAS of total cholesterol in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), when testing all SNPs with P‐values <5×10−8 (15 genomic regions) for generalization in a large GWAS of whites, we generalized SNPs from 15 regions. But when testing all SNPs with P‐values <6.6×10−5 (89 regions), we generalized SNPs from 27 regions.

Sex-influenced association of nonalcoholic fatty liver disease with coronary heart disease.

OBJECTIVE This study investigated whether nonalcoholic fatty liver disease (NAFLD) predicts prevalent coronary heart disease (CHD). METHODS Epidemiologic studies have used various definitions for NAFLD. Here, we considered both liver fat burden measured by CT (FL) and the non-specific measure of hepatic inflammation -alanine aminotransferase (ALT). The association of FL and ALT with CHD (self report of coronary bypass, myocardial infarction, or percutaneous transluminal coronary angioplasty) was investigated in 2756 European-American participants of the Family Heart Study. RESULTS FL (p = 0.0084) and ALT (≥40 U/L, p = 0.014) were each individually associated with prevalent CHD. However, when accounting for traditional metabolic risk factors in a multivariate model FL had no predictive value for CHD in either men or women; whereas ALT was a significant predictor of CHD in men, and the association strengthened among non-diabetic men. In non-diabetic women, neither FL nor ALT was associated with CHD. CONCLUSIONS ALT (≥40 U/L) was a predictor of prevalent CHD in men but not in women, while CT measured FL was not significant in either sex. The failure to account for traditional risk factors, heterogeneity by sex, and varying definitions of NAFLD may account for some of the conflicting evidence in the literature regarding the association between NAFLD and coronary disease.

Genetic Association Analysis under Complex Survey Sampling: The Hispanic Community Health Study/Study of Latinos

The cohort design allows investigators to explore the genetic basis of a variety of diseases and traits in a single study while avoiding major weaknesses of the case-control design. Most cohort studies employ multistage cluster sampling with unequal probabilities to conveniently select participants with desired characteristics, and participants from different clusters might be genetically related. Analysis that ignores the complex sampling design can yield biased estimation of the genetic association and inflation of the type I error. Herein, we develop weighted estimators that reflect unequal selection probabilities and differential nonresponse rates, and we derive variance estimators that properly account for the sampling design and the potential relatedness of participants in different sampling units. We compare, both analytically and numerically, the performance of the proposed weighted estimators with unweighted estimators that disregard the sampling design. We demonstrate the usefulness of the proposed methods through analysis of MetaboChip data in the Hispanic Community Health Study/Study of Latinos, which is the largest health study of the Hispanic/Latino population in the United States aimed at identifying risk factors for various diseases and determining the role of genes and environment in the occurrence of diseases. We provide guidelines on the use of weighted and unweighted estimators, as well as the relevant software.

Childhood nutrition and later fertility: Pathways through education and pre-pregnant nutritional status

Better childhood nutrition is associated with earlier physical maturation during adolescence and increased schooling attainment. However, as earlier onset of puberty and increased schooling can have opposing effects on fertility, the net effect of improvements in childhood nutrition on a woman’s fertility are uncertain. Using path analysis, we estimate the strength of the pathways between childhood growth and subsequent fertility outcomes in Guatemalan women studied prospectively since birth. Height for age z score at 24 months was positively related to body mass index (BMI kg/m2) and height (cm) in adolescence and to schooling attainment. BMI was negatively associated (−0.23 ± 0.09 years per kg/m2; p < . 05) and schooling was positively associated (0.38 ± 0.06 years per grade; p < .001) with age at first birth. Total associations with the number of children born were positive from BMI (0.07 ± 0.02 per kg/m2; p < .05) and negative from schooling (−0.18 ± 0.02 per grade; p < .01). Height was not related to age at first birth or the number of children born. Taken together, childhood nutrition, as reflected by height at 2 years, was positively associated with delayed age at first birth and fewer children born. If schooling is available for girls, increased growth during childhood will most likely result in a net decrease infertility.