Tsegaselassie Workalemahu

Quality control and conduct of genome-wide association meta-analyses

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Novel locus including FGF21 is associated with dietary macronutrient intake

Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10(-5)) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10(-9)). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake.

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.

Genetic Determinants for Body Iron Store and Type 2 Diabetes Risk in US Men and Women

Background High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk. Methodology/Principal Findings Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses’ Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47×10−6), TF with transferrin (P = 0.0002 to 1.72×10−10); and HFE with ferritin (P = 0.017 to 1.6×10−8), sTfR (P = 0.007 to 7.9×10−6), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66–0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk. Conclusions/Significance The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.

Birth Weight, Genetic Susceptibility, and Adulthood Risk of Type 2 Diabetes

OBJECTIVE Both stressful intrauterine milieus and genetic susceptibility have been linked to later-life diabetes risk. The current study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterine milieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS The analysis included two independent, nested case-control studies of 2,591 type 2 diabetic case subjects and 3,052 healthy control subjects. We developed two genotype scores: an obesity genotype score based on 32 BMI-predisposing variants and a diabetes genotype score based on 35 diabetes-predisposing variants. RESULTS Obesity genotype scores showed a stronger association with type 2 diabetes risk in individuals with low birth weight. In low–birth weight individuals, the multivariable-adjusted odds ratio (OR) was 2.55 (95% CI 1.34–4.84) by comparing extreme quartiles of the obesity genotype score, while the OR was 1.27 (1.04–1.55) among individuals with birth weight >2.5 kg (P for interaction = 0.017). We did not observe significant interaction between diabetes genotype scores and birth weight with regard to risk of type 2 diabetes. In a comparison of extreme quartiles of the diabetes gene score, the multivariable-adjusted OR was 3.80 (1.76–8.24) among individuals with low birth weight and 2.27 (1.82–2.83) among those with high birth weight (P for interaction = 0.16). CONCLUSIONS Our data suggest that low birth weight and genetic susceptibility to obesity may synergistically affect adulthood risk of type 2 diabetes.

Genetic variants near the IRS1 gene, physical activity and type 2 diabetes in US men and women

Abbreviations HPFS Health Professionals Follow-up Study IRS1 Insulin receptor substrate 1 LD Linkage disequilibrium MET Metabolic equivalent task NHS Nurses’ Health Study SNP Single nucleotide polymorphism To the Editor: Insulin receptor substrate 1 (IRS1) plays a key role in the insulin-stimulated signal transduction pathway [1]. Recently, a genome-wide association study showed that a variant (rs2943641) near the IRS1 gene was associated with insulin resistance, hyperinsulinaemia and the risk of type 2 diabetes [2]. In this study, we comprehensively examined the associations of the variants near the IRS1 gene with type 2 diabetes risk in two nested case–control studies from the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Because physical activity may modify the genetic effects on diabetes [3] and enhance insulin activation of IRS1-associated phosphatidylinositol 3-kinase activity [4], we further examined the gene– physical activity interactions in relation to the risk of diabetes. Type 2 diabetes cases were identified by self-report methods that were confirmed with a validated supplementary questionnaire. The study was approved by the Human Research Committee at the Brigham and Women’s Hospital, Boston. General information was derived from the baseline questionnaire. Physical activity was expressed as metabolic equivalent task (MET) h of moderate to vigorous exercise per week in men, and as h/week in women because MET was not measured at baseline. We used genotyping data from a genome-wide scan. We examined associations with type 2 diabetes for the single-nucleotide polymorphisms (SNPs) near the reported SNP rs2943641 [2] (electronic supplementary material [ESM] Fig. 1). We used logistic regression to estimate ORs after adjustment for potential risk factors. An additive genetic model was applied in the first instance. Tests of interaction between SNPs and physical activity were assessed by including the cross-product of Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2123-7) contains supplementary material, which is available to authorised users. M. A. He : T. Workalemahu :M. C. Cornelis : F. B. Hu : L. Qi (*) Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA e-mail: nhlqi@channing.harvard.edu

Genome-wide and candidate gene association studies of placental abruption

Placental abruption (PA), a pregnancy-related vascular disorder, is a leading cause of maternal and perinatal morbidity and mortality. The success of identifying genetic susceptibility loci for PA, a multi-factorial heritable disorder, has been limited. We conducted a genome-wide association study (GWAS) and candidate gene association study using 470 PA cases and 473 controls from Lima, Peru. Genotyping for common genetic variations (single nucleotide polymorphisms, SNPs) was conducted using the Illumina Cardio-Metabo Chip platform. Common variations in 35 genes that participate in mitochondrial biogenesis (MB) and oxidative phosphorylation (OS) were selected for the candidate gene study. Regression models were fit to examine associations of each SNP with risk of PA. In pathway analyses, we examined functions and functional relationships of genes represented by the top GWAS hits. Genetic risk scores (GRS), based on top hits of the GWAS and candidate gene analyses, respectively, were computed using the risk allele counting method. The top hit in the GWAS analyses was rs1238566 (empirical P-value=1.04e-4 and FDR-adjusted P-value=5.65E-04) in FLI-1 gene, a megakaryocyte-specific transcription factor. Networks of genes involved in lipid metabolism and cell signaling were significantly enriched by the 51 genes whose SNPs were among the top 200 GWAS hits (P-value <2.1e-3). SNPs known to regulate MB (e.g. CAMK2B, NR1H3, PPARG, PRKCA, and THRB) and OP (e.g., COX5A, and NDUF family of genes) were associated with PA risk (P-value <0.05). GRS was significantly associated with PA risk (trend P-value <0.001 and 0.01 for GWAS and candidate gene based GRS, respectively). Our study suggests that integrating multiple analytical strategies in genetic association studies can provide opportunities for identifying genetic risk factors and novel molecular mechanisms that underlie PA.

Physical Activity and Metabolic Syndrome among Ethiopian Adults

BACKGROUND The global prevalence of chronic noncommunicable diseases (NCDs) is on the rise, with the majority of the growth occurring among populations in developing countries. Few studies have quantified the health benefits for physical activity among sub-Saharan African adults. We examined associations of physical activity with the prevalence of metabolic syndrome (MetS) and its components in Ethiopian men and women. METHODS This cross-sectional study of 1,843 individuals (1,117 men and 726 women) was conducted among working adults (public schools and bank employees) in Addis Ababa, Ethiopia. The study was conducted in accordance with the STEPwise approach of the World Health Organization. Physical activity was assessed using a previously validated Global Physical Activity Questionnaire. MetS was defined according to the International Diabetes Federation criteria. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). RESULTS The odds of MetS was inversely associated with physical activity in men (P trend = 0.02) but not women (P trend = 0.85). Among men, the OR of MetS comparing those with high vs. low levels of physical activity was 0.56 (95% CI = 0.33-0.97). For women, the corresponding OR was 1.07 (95% CI = 0.57-2.01). Physical activity was significantly and inversely associated with high waist circumference and hypertriglyceridemia among men, but no such associations were observed among women. CONCLUSIONS Higher levels of physical activity were inversely associated with MetS and several individual components among men. No similar trends were observed among women in this cohort, in part because of the small sample size.