Lack of relationship between mitochondrial heteroplasmy or variation and childhood obesity.

Mitochondrial electron transport has a central role in regulating energy supply within a cell. We hypothesized that mitochondrial variants or increased levels of mitochondrial heteroplasmy could be associated with common childhood obesity through their effects on mitochondrial function. To investigate this question, we queried two genome-wide genotyped childhood obesity datasets, consisting of 1080 European-American (EA) obese children (defined as BMI ≥ 95th percentile) together with 2500 EA lean controls (defined as BMI<50th percentile) and 1479 African-American (AA) obese children and 1575 AA lean controls.

Mosaic trisomy 17: variable clinical and cytogenetic presentation.

Mosaic trisomy 17 is rare with only 28 cases reported and the clinical presentation is highly variable. The diagnosis is most commonly made by prenatal karyotype and in most cases is followed by a normal postnatal karyotype on blood lymphocytes.We present two cases of mosaic trisomy 17 diagnosed prenatally,with follow up in multiple tissues at birth.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants.

A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci.

Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.

Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.

Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.

Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21, CCL5, GNLY, SLAMF7, TGFBR3, NKG7, SYNE1, and GK5.

Crohn's disease and genetic hitchhiking at IBD5.

Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET.

SNVer: a statistical tool for variant calling in analysis of pooled or individual next-generation sequencing data.

We develop a statistical tool SNVer for calling common and rare variants in analysis of pooled or individual next-generation sequencing (NGS) data. We formulate variant calling as a hypothesis testing problem and employ a binomial-binomial model to test the significance of observed allele frequency against sequencing error. SNVer reports one single overall P-value for evaluating the significance of a candidate locus being a variant based on which multiplicity control can be obtained.

Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications.

Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them.

Convergent mechanisms of somatic mutations in polycythemia vera.

Polycythemia vera (PV) is an acquired blood disorder, with variable increase of clonal myeloid cells (erythrocytes, granulocytes and platelets) and mostly normal polyclonal T lymphocytes. Most patients have a somatic V617F gain-of-function mutation in JAK2 associated with acquired uniparental disomy (UPD) on chromosome 9p. Yet, the JAK2 V617F mutation is not a PV-initiating event and the family clustering of PV suggests a contribution of inherited genetic events.

Role of BMI-associated loci identified in GWAS meta-analyses in the context of common childhood obesity in European Americans.

Obesity is a serious health concern for children and adolescents, particularly in Western societies, where its incidence is now considered to have reached epidemic proportions. A number of genetic determinants of adult BMI have already been established through genome wide association studies (GWAS), most recently from the GIANT meta-analysis of such datasets combined. In this current study of European Americans, we examined the 32 loci detected in that GIANT study in the context of common childhood obesity within a cohort of 1,097 cases (defined as BMI ≥95th percentile), together with 2,760 lean controls (defined as BMI <50th percentile), aged between 2 and 18 years old.

The landscape of recombination in African Americans.

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans.

Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma.

Background: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene.

Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.

We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports.

Fatty-acid binding protein 4 gene polymorphisms and plasma levels in children with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) is associated with increased risk for metabolic syndrome in both adults and children. In adults with OSA, serum levels of fatty acid binding protein 4 (FABP4) are elevated and associated with the degree of metabolic insulin resistance, independent of obesity. Therefore, we assessed plasma FABP4 levels and FABP4 allelic variants in obese and non-obese children with and without OSA.

Genome-wide association studies (GWAS): impact on elucidating the aetiology of diabetes.

It has proven to be challenging to isolate the genes underlying the genetic components conferring susceptibility to type 1 and type 2 diabetes. Unlike previous approaches, 'genome-wide association studies' have extensively delivered on the promise of uncovering genetic determinants of complex diseases, with a number of novel disease-associated variants being largely replicated by independent groups. This review provides an overview of these recent breakthroughs in the context of type 1 and type 2 diabetes, and outlines strategies on how these findings will be applied to impact clinical care for these two highly prevalent disorders.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)).

Planning a genome-wide association study: points to consider.

It is well established that genetic diversity combined with specific environmental exposures contributes to disease susceptibility. However, it has turned out to be challenging to isolate the genes underlying the genetic component conferring susceptibility to most complex disorders. Traditional candidate gene and family-based linkage studies, which dominated gene discovery efforts for many years, were largely unsuccessful in unraveling the genetics of these traits due to the relatively limited information gained.

A genome-wide association study on obesity and obesity-related traits.

Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m(2)) and 540 control subjects (BMI<25 kg/m(2)), on measures of obesity and obesity-related traits.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus.

Genome-wide association identifies diverse causes of common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities.

Objective: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID.

Methods: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs).