👤 Tsegaselassie Workalemahu

Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data. Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10 This study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases. Show less

Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae. The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated. The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex. Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×10 In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae. Show less

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. Show less

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. Show less

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. Show less