A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide associatio Show more
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Show less
Several antipsychotic drugs (APDs) have high propensity to induce weight gain and dyslipidemia in patients, with clozapine and olanzapine as the most potent drugs. These lipid-related effects have bee Show more
Several antipsychotic drugs (APDs) have high propensity to induce weight gain and dyslipidemia in patients, with clozapine and olanzapine as the most potent drugs. These lipid-related effects have been attributed to drug-mediated blockade or antagonism of histamine H1 and serotonin 5-HT2 receptors as well as activation of hypothalamic AMP-activated protein kinase. We recently showed that APDs activate lipid biosynthesis in cultured liver cells through stimulation of the sterol regulatory element-binding protein (SREBP) transcription factors. The objective of the study was to search for clozapine-related lipogenic effects in peripheral tissues in vivo using rat liver as target organ. Adult female Sprague-Dawley rats were administered single intraperitoneal injections of clozapine (25 and 50 mg/kg). Hepatic lipid levels were measured during a 48-h time course. Real-time quantitative PCR was used to analyze expression of genes involved in lipid biosynthesis, oxidation, efflux, and lipolysis. We identified an initial up-regulation of central lipogenic SREBP target genes, followed by a marked and sustained down-regulation. We also observed a sequential transcriptional response for fatty acid beta-oxidation and cholesterol efflux genes, normally controlled by the peroxisome proliferator activated receptor alpha and liver X receptor alpha transcription factors, and also down-regulation of genes encoding major lipases. The transcriptional responses were associated with a significant accumulation of triacylglycerol, phospholipids, and cholesterol in the liver. These results demonstrate that acute clozapine exposure affects SREBP-regulated lipid biosynthesis as well as other lipid homeostasis pathways. We suggest that such drug-induced effects on lipid metabolism in peripheral tissues are relevant for the metabolic adverse effects associated with clozapine and possibly other APDs. Show less