LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity.

Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic-pituitary-adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e.

Design, analysis, and interpretation of treatment response heterogeneity in personalized nutrition and obesity treatment research.

It is increasingly assumed that there is no one-size-fits-all approach to dietary recommendations for the management and treatment of chronic diseases such as obesity. This phenomenon that not all individuals respond uniformly to a given treatment has become an area of research interest given the rise of personalized and precision medicine. To conduct, interpret, and disseminate this research rigorously and with scientific accuracy, however, requires an understanding of treatment response heterogeneity.

Comorbidity of Novel Gene Variants in Type 2 Diabetes and Depression.

The corticotropin-releasing hormone receptor 2 () gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. mice are hypersensitive to stress, and the locus has been linked to type 2 diabetes and depression. While variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD.

Childhood maltreatment, serotonin transporter gene, and risk for callous and unemotional traits: A prospective investigation.

Previous studies have reported associations between the serotonin transporter 5-HTTLPR genotype and antisocial and aggressive traits and between child maltreatment and antisocial traits. However, few studies have examined whether 5-HTTLPR moderates the influence of childhood maltreatment on callous and unemotional traits, a hallmark of psychopathy. Using a prospective cohort design, children with documented cases of maltreatment and matched controls were followed up and interviewed in adulthood.

A reliable method to determine which candidate chemotherapeutic drugs effectively inhibit tumor growth in patient-derived xenografts (PDX) in single mouse trials.

Purpose: We report on a statistical method for grouping anti-cancer drugs (GRAD) in single mouse trials (SMT). The method assigns candidate drugs into groups that inhibit or do not inhibit tumor growth in patient-derived xenografts (PDX). It determines the statistical significance of the group assignments without replicate trials of each drug.

Bone marrow-derived epithelial cells and hair follicle stem cells contribute to development of chronic cutaneous neoplasms.

We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). BMDECs clustered in the lesional epithelium, expressed cytokeratins, proliferated, and stratified. We detected cytokeratin induction in plastic-adherent bone marrow cells (BMCs) cultured in the presence of filter-separated keratinocytes (KCs) and bone morphogenetic protein 5 (BMP5).

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings).

An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance.

Our motivation here is to calculate the power of 3 statistical tests used when there are genetic traits that operate under a pleiotropic mode of inheritance and when qualitative phenotypes are defined by use of thresholds for the multiple quantitative phenotypes. Specifically, we formulate a multivariate function that provides the probability that an individual has a vector of specific quantitative trait values conditional on having a risk locus genotype, and we apply thresholds to define qualitative phenotypes (affected, unaffected) and compute penetrances and conditional genotype frequencies based on the multivariate function. We extend the analytic power and minimum-sample-size-necessary (MSSN) formulas for 2 categorical data-based tests (genotype, linear trend test [LTT]) of genetic association to the pleiotropic model.

Expression and characterization of three Aurora kinase C splice variants found in human oocytes.

Chromosome segregation is an extensively choreographed process yet errors still occur frequently in female meiosis, leading to implantation failure, miscarriage or offspring with developmental disorders. Aurora kinase C (AURKC) is a component of the chromosome passenger complex and is highly expressed in gametes. Studies in mouse oocytes indicate that AURKC is required to regulate chromosome segregation during meiosis I; however, little is known about the functional significance of AURKC in human oocytes.

A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.

Deficits in Trabecular Bone Microarchitecture in Young Women With Type 1 Diabetes Mellitus.

The pathophysiological mechanism of increased fractures in young adults with type 1 diabetes mellitus (T1DM) is unclear. We conducted a case-control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Thirty women with T1DM with a median age (range) age of 22.

Mapping genes with longitudinal phenotypes via Bayesian posterior probabilities.

Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies.

Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model.

Objective: To assess the effectiveness of l-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in an Slc3a1 knockout mouse model of cystinuria.

Materials And Methods: CDME (200 μg per mouse) or water was delivered by gavage daily for 4 weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity.

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups.

Background: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls.

A novel method for analyzing genetic association with longitudinal phenotypes.

Knowledge of genes influencing longitudinal patterns may offer information about predicting disease progression. We developed a systematic procedure for testing association between SNP genotypes and longitudinal phenotypes. We evaluated false positive rates and statistical power to localize genes for disease progression.

A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse.

The multistage model of nonmelanoma skin carcinogenesis has contributed significantly to our understanding of epithelial cancer in general. We used the Krt1-15CrePR1;R26R transgenic mouse to determine the contribution of keratin 15+ cells from the hair follicle to skin tumor development by following the labeled progeny of the keratin 15 expressing cells into papillomas. We present three novel observations.

IL-18R1 and IL-18RAP SNPs may be associated with bronchopulmonary dysplasia in African-American infants.

Introduction: The genetic contribution to the development of bronchopulmonary dysplasia (BPD) in prematurely born infants is substantial, but information related to the specific genes involved is lacking.

Results: Genotype analysis revealed, after multiple comparisons correction, two significant single-nucleotide polymorphism (SNPs), rs3771150 (IL-18RAP) and rs3771171 (IL-18R1), in African Americans (AAs) with BPD (vs. AAs without BPD; q < 0.

TDT-HET: a new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data.

Background: Locus heterogeneity is one of the most documented phenomena in genetics. To date, relatively little work had been done on the development of methods to address locus heterogeneity in genetic association analysis. Motivated by Zhou and Pan's work, we present a mixture model of linked and unlinked trios and develop a statistical method to estimate the probability that a heterozygous parent transmits the disease allele at a di-allelic locus, and the probability that any trio is in the linked group.

Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error.

As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing.

A new expectation-maximization statistical test for case-control association studies considering rare variants obtained by high-throughput sequencing.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation reproducibly associated with disease. However, most associated variants confer very small risk and after meta-analysis of large cohorts a large fraction of expected heritability still remains unexplained. A possible explanation is that rare variants currently undetected by GWAS with SNP arrays could contribute a large fraction of risk when present in cases.