Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Recherche des facteurs génétiques à l’origine de la maladie de Parkinson dans la population canadienne-française du Québec

La maladie de Parkinson (MP) est une affection neurodégénérative invalidante et incurable. Il est maintenant clairement établi que d’importants déterminants génétiques prédisposent à son apparition. La recherche génétique sur des formes familiales de la MP a mené à la découverte d’un minimum de six gènes causatifs (SNCA, LRRK2, Parkin, PINK1, DJ-1 and GBA) et certains, par exemple LRRK2, contiennent des variations génétiques qui prédisposent également aux formes sporadiques. La caractérisation des protéines codées par ces gènes a mené à une meilleure compréhension des mécanismes moléculaires sousjacents. Toutefois, en dépit de ces efforts, les causes menant à l’apparition de la MP restent inconnues pour la majorité des patients. L’objectif général des présents travaux était d’identifier des mutations prédisposant à la MP dans la population canadienne-française du Québec à partir d’une cohorte composée principalement de patients sporadiques. Le premier volet de ce projet consistait à déterminer la présence de mutations de LRRK2 dans notre cohorte en séquençant directement les exons contenant la majorité des mutations pathogéniques et en effectuant une étude d’association. Nous n’avons identifié aucune mutation et l’étude d’association s’est avérée négative, suggérant ainsi que LRRK2 n’est pas une cause significative de la MP dans la population canadienne-française. La deuxième partie du projet avait pour objectif d’identifier de nouveaux gènes causatifs en séquençant directement des gènes candidats choisis à cause de leurs implications dans différents mécanismes moléculaires sous-tendant la MP. Notre hypothèse de recherche était basée sur l’idée que la MP est principalement due à des mutations individuellement rares dans un grand nombre de gènes différents. Nous avons identifié des mutations rares dans les gènes PICK1 et MFN1. Le premier code pour une protéine impliquée dans la régulation de la transmission du glutamate tandis que le second est un des acteurs-clés du processus de fusion mitochondriale. Nos résultats, qui devront être répliqués, suggèrent que le séquençage à grande échelle pourrait être une méthode prometteuse d’élucidation des facteurs de prédisposition génétiques à la MP ; ils soulignent l’intérêt d’utiliser une population fondatrice comme les canadiens-français pour ce type d’étude et devraient permettre d’approfondir les connaissances sur la pathogénèse moléculaire de la MP.

Etude des déterminants génétiques des psychoses à début précoce. Génétique de la schizophrénie et hypothèse glutamatergique

Les troubles schizophréniques (SCZ) ont une forte héritabilité, de l’ordre de 80%, mais, une très faible part du risque génétique a été identifiée. La plupart des études ont considéré l’implication de polymorphismes fréquents, chacun ayant un effet relativement faible individuellement, alors que les études de variants du nombre de copies (CNVs) ainsi que les études d’anomalies chromosomiques ont pointé l’implication possible de variants rares et de novo à une forte pénétrance. Dans une première partie, nous présentons une synthèse sur les facteurs génétiques dans la SCZ, puis une revue des arguments en faveur de l’implication d’anomalies du système glutamatergique dans la SCZ, domaine sur lequel s’est centré notre travail. Notre travail s’inscrit dans un projet plus vaste, Synapse to Disease (S2D) ayant pour objectif de séquencer 1000 gènes synaptiques dans des cohortes de patients atteints de schizophrénie ou de troubles du spectre autistique. Nous avons exploré en particulier le système glutamatergique et les récepteurs NMDA. Dans un premier article, nous montrons une association d’une mutation troncante de novo de la kinésine 17, impliquée dans le transport de la sous-unité GRIN2B des récepteurs NMDA. Dans un second article, nous explorons les mutations rares et de novo dans les sous-unités des récepteurs NMDA et montrons l’association de mutation de novo dans GRIN2A et GRIN2B avec des cas de SCZ et d’autisme. Nos résultats renforcent l’idée qu’une part des cas de schizophrénie pourrait être due à l’implication de mutations rare à effet majeur, hypothèse alternative mais non exclusive à l’hypothèse d’interactions entre variants génétiques fréquents à effet mineur.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Genome-wide association study of response to cognitive behavioural therapy in children with anxiety disorders

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5×10−8) in either analysis. Four variants met criteria for suggestive significance (P<5×10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes

The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia. The human homologue of BEACON is located on chromosome 19p, a region likely to contain genes affecting metabolic syndrome–related quantitative traits as established by linkage studies. To assess whether the human BEACON gene may be involved in influencing these traits, we exhaustively analyzed the complete gene for genetic variation in 40 unrelated individuals and identified four variants (three novel). The two more common variants were tested for association with a number of quantitative metabolic syndrome–related traits in two large cohorts of unrelated individuals. Significant associations were found between these variants and fat mass (P = 0.026), percentage of fat (P = 0.001), and waist-to-hip ratio (P = 0.031). The same variants were also associated with total cholesterol (P = 0.024), LDL cholesterol (P = 0.019), triglycerides (P = 0.006), and postglucose load insulin levels (P = 0.018). Multivariate analysis of these correlated phenotypes also yielded a highly significant association (P = 0.0004), suggesting that BEACON may influence phenotypic variation in metabolic syndrome–related traits.

Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture

The aim of this study was to determine if DNA polymorphism within runt-related gene 2 (RUNX2)/core binding factor A1 (CBFA1) is related to bone mineral density (BMD). RUNX2 contains a glutamine-alanine repeat where mutations causing cleidocranial dysplasia (CCD) have been observed. Two common variants were detected within the alanine repeat: an 18-bp deletion and a synonymous alanine codon polymorphism with alleles GCA and GCG (noted as A and G alleles, respectively). In addition, rare mutations that may be related to low BMD were observed within the glutamine repeat. In 495 randomly selected women of the Geelong Osteoporosis Study (GOS), the A allele was associated with higher BMD at all sites tested. The effect was maximal at the ultradistal (UD) radius (p = 0.001). In a separate fracture study, the A allele was significantly protective against Colles' fracture in elderly women but not spine and hip fracture. The A allele was associated with increased BMD and was protective against a common form of osteoporotic fracture, suggesting that RUNX2 variants may be related to genetic effects on BMD and osteoporosis.

Polimorfismos dos genes ADA e CNTNAP2 em indivíduos com Transtornos do Espectro do Autismo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease

Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the HoltOram syndrome (hearthand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned approximate to 700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the HoltOram syndrome, and identified a patient with a homozygous mutation in an enhancer approximate to 90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the HoltOram syndrome.

Allelic variations in the vitamin D receptor gene, insulin secretion and parents' heights are independently associated with height in obese children and adolescents

Polymorphisms in the VDR gene were reported to be associated with variations in intrauterine and postnatal growth and with adult height, but also with other traits that are strongly correlated such as the BMI, insulin sensitivity, insulin secretion and hyperglycemia. Here, we assessed the impact of VDR polymorphisms on body height and its interactions with obesity- and glucose tolerance-related traits in obese children and adolescents. We studied 173 prepubertal (Tanner's stage 1) and 146 pubertal (Tanner's stages 2-5) obese children who were referred for a weight-loss program. Three single nucleotide polymorphisms were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). BsmI and TaqI genotypes were significantly associated with height in pubertal children, but the associations did not reach statistical significance in prepubertal children. In stepwise regression analyses, the lean body mass, insulin secretion, BsmI or TaqI genotypes and the father's and the mother's height were independently and positively associated with height in pubertal children. These covariables accounted for 46% of the trait variance. The height of homozygous carriers of the minor allele of BsmI was 0.65 z-scores (4 cm) higher than the height of homozygous carriers of the major allele (P=.0006). Haplotype analyses confirmed the associations of the minor alleles of BsmI and TaqI with increased height. In conclusion, VDR genotypes were significantly associated with height in pubertal obese children. The associations were independent from the effects of confounding traits, such as the body fat mass, insulin secretion, insulin sensitivity and glucose tolerance. (C) 2012 Elsevier Inc. All rights reserved.

Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk

Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC. Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk. Physiol Genomics 44: 903-914, 2012. First published August 7, 2012; doi:10.1152/physiolgenomics.00030.2012.-The single nucleotide polymorphism (SNP) within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker associated with Type 2 diabetes mellitus (T2DM) risk. Nonetheless, its functional role in disease pathology is poorly understood. The aim of the present study was to investigate, in vascular smooth muscle cells from 92 patients undergoing aortocoronary bypass surgery, the contribution of this SNP in T2DM using expression levels and expression correlation comparison approaches, which were visually represented as gene interaction networks. Initially, the expression levels of 41 genes (seven TCF7L2 splice forms and 40 other T2DM relevant genes) were compared between rs7903146 wild-type (CC) and T2DM-risk (CT + TT) genotype groups. Next, we compared the expression correlation patterns of these 41 genes between groups to observe if the relationships between genes were different. Five TCF7L2 splice forms and nine genes showed significant expression differences between groups. RXR alpha gene was pinpointed as showing the most different expression correlation pattern with other genes. Therefore, T2DM risk alleles appear to be influencing TCF7L2 splice form's expression in vascular smooth muscle cells, and RXR alpha gene is pointed out as a treatment target candidate for risk reduction in individuals with high risk of developing T2DM, especially individuals harboring TCF7L2 risk genotypes.

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls

To identify a classifier in schizophrenia, blood gene expression profiling was applied to patients with schizophrenia under different treatments and to controls. Expression of six genes discriminated patients with sensitivity of 89.3% and specificity of 90%, supporting the use of peripheral blood as biological material for diagnosis in schizophrenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Association of GWAS loci with PD in China

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case-control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS-linked data and research on ethnic specific effect of common variants.

Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women

Associations between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (−703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of two TPH2 SNPs, namely rs4570625 (−703 G/T) and rs2129575 (p≤0.0004) and the C-allele frequency of one TPH2 SNP, namely rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (−703 G/T), rs2129575 and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.