BMD-associated variation at the Osterix locus is correlated with childhood obesity in females.

Recent genome wide association studies (GWAS) have revealed a number of genetic variants robustly associated with bone mineral density (BMD) and/or osteoporosis. Evidence from epidemiological and clinical studies has shown an association between BMD and BMI, presumably as a consequence of bone loading. We investigated the 23 previously published BMD GWAS-derived loci in the context of childhood obesity by leveraging our existing genome-wide genotyped European American cohort of 1106 obese children (BMI ≥ 95th percentile) and 5997 controls (BMI < 95th percentile).

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.

Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder.

Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.

The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility.

Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein that regulates Itch, an E3 ubiquitin ligase that ubiquitylates JunB, thereby preventing interleukin (IL)-4 and IL-5 production. Mice lacking Ndfip1 or Itch develop T helper type 2 (T(H)2)-mediated inflammation in the skin and lungs and die prematurely. In this study we show that Ndfip1-/- mice also develop inflammation in the gastrointestinal tract.

A genome-wide study reveals copy number variants exclusive to childhood obesity cases.

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Genomic copy number variations (CNVs) have been strongly implicated in subjects with extreme obesity and coexisting developmental delay. To complement these previous studies, we addressed CNVs in common childhood obesity by examining children with a BMI in the upper 5(th) percentile but excluding any subject greater than three standard deviations from the mean in order to reduce severe cases in the cohort.

The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature.

Background: Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies.

Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes.

In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium.

Recently, the Type 1 Diabetes Genetics Consortium (T1DGC) reported 22 novel type 1 diabetes (T1D)-associated loci identified by meta-analysis of three genome-wide association studies (GWASs) with a case-control design. However, the association of 10 of these 22 reported loci was not confirmed in the T1DGC family cohort (P > 0.1).

Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition.

Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.

Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk.

Variants of DENND1B associated with asthma in children.

Background: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.

Methods: We carried out a genomewide association study involving children with asthma.

The type I diabetes association of the IL2RA locus.

To confirm and fine map previous reports of association, the Type I Diabetes (T1D) Genetics Consortium (T1DGC) assembled a large collection of DNA samples from affected sib-pair (ASP) families with T1D (5003 affected individuals) and genotyped polymorphic markers. One of these loci, involving the IL2RA gene, had been reported to be due to three independent effects. The T1DGC genotyped 69 single-nucleotide polymorphisms (SNPs) that span approximately 88 kb from the 5' flanking to 3' flanking region of the IL2RA locus.

Remapping the type I diabetes association of the CTLA4 locus.

The Type I Diabetes Genetics Consortium genotyped 24 single-nucleotide polymorphisms (SNPs) in the CTLA4 locus in 2298 type I diabetes (T1D) nuclear families (11 159 individuals, 5003 affected) to evaluate the recognized T1D association. The 24 CTLA4 SNPs span approximately 43 kb from the 5' flanking to 3' flanking region of the gene in the middle of an extended region of linkage disequilibrium of more than 100 kb. The genotyping was performed using two technologies (Illumina GoldenGate and Sequenom iPlex) on the same samples.

Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI.

Objective: A number of studies have found that BMI in early life influences the risk of developing type 2 diabetes later in life. Our goal was to investigate if any type 2 diabetes variants uncovered through genome-wide association studies (GWAS) impact BMI in childhood.

Research Design And Methods: Using data from an ongoing GWAS of pediatric BMI in our cohort, we investigated the association of pediatric BMI with 20 single nucleotide polymorphisms at 18 type 2 diabetes loci uncovered through GWAS, consisting of ADAMTS9, CDC123-CAMK1D, CDKAL1, CDKN2A/B, EXT2, FTO, HHEX-IDE, IGF2BP2, the intragenic region on 11p12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5.

Common variants at five new loci associated with early-onset inflammatory bowel disease.

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.

From disease association to risk assessment: an optimistic view from genome-wide association studies on type 1 diabetes.

Genome-wide association studies (GWAS) have been fruitful in identifying disease susceptibility loci for common and complex diseases. A remaining question is whether we can quantify individual disease risk based on genotype data, in order to facilitate personalized prevention and treatment for complex diseases. Previous studies have typically failed to achieve satisfactory performance, primarily due to the use of only a limited number of confirmed susceptibility loci.

A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24.

Objective: To identify, in a non-hypothesis manner, novel genetic factors associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P).

Study Design: We performed a genome-wide association study in a pediatric cohort of European decent consisting of 111 NSCL/P cases and 5951 control subjects. All subjects were consecutively recruited from the Greater Philadelphia area from 2006 to 2009.

High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications.

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and African-Americans (34.

Examination of type 2 diabetes loci implicates CDKAL1 as a birth weight gene.

Objective: A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk-conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait.