Characteristics of replicated single-nucleotide polymorphism genotypes from COGA: Affymetrix and Center for Inherited Disease Research

Genetic Analysis Workshop 14 provided re-genotyped single-nucleotide polymorphism (SNP) data. Specifically, both Center for Inherited Disease Research (CIDR) and Affymetrix genotyped the same 11,560 SNPs from the Affymetrix GeneChip Mapping 10K Array marker set on the same 184 individuals from the Collaborative Study on the Genetics of Alcoholism database. While the inconsistency rate between CIDR and Affymetrix (two different genotypes for the same subject) was low (0.2%), the non-replication rate (two different genotypes for the same subject or one identified genotype and one missing genotype) was substantial (9.5%). The missing data could be from no-call regions, which is inconsistent with recent recommendations about the use of no-call regions in association tests. In addition, no-call regions would suggest that the actual inconsistency rate is higher than reported. A high inconsistency rate has significant impact on power in related hypothesis tests. In addition, the data are consistent with assumptions made in a recently proposed likelihood ratio test of association for re-genotyped data

Mixture modeling of microarray gene expression data

About 28% of genes appear to have an expression pattern that follows a mixture distribution. We use first- and second-order partial correlation coefficients to identify trios and quartets of non-sex-linked genes that are highly associated and that are also mixtures. We identified 18 trio and 35 quartet mixtures and evaluated their mixture distribution concordance. Concordance was defined as the proportion of observations that simultaneously fall in the component with the higher mean or simultaneously in the component with the lower mean based on their Bayesian posterior probabilities. These trios and quartets have a concordance rate greater than 80%. There are 33 genes involved in these trios and quartets. A factor analysis with varimax rotation identifies three gene groups based on their factor loadings. One group of 18 genes has a concordance rate of 56.7%, another group of 8 genes has a concordance rate of 60.8%, and a third group of 7 genes has a concordance rate of 69.6%. Each of these rates is highly significant, suggesting that there may be strong biological underpinnings for the mixture mechanisms of these genes. Bayesian factor screening confirms this hypothesis by identifying six single-nucleotide polymorphisms that are significantly associated with the expression phenotypes of the five most concordant genes in the first group

Growth mixture modeling as an exploratory analysis tool in longitudinal quantitative trait loci analysis

We examined the properties of growth mixture modeling in finding longitudinal quantitative trait loci in a genome-wide association study. Two software packages are commonly used in these analyses: Mplus and the SAS TRAJ procedure. We analyzed the 200 replicates of the simulated data with these programs using three tests: the likelihood-ratio test statistic, a direct test of genetic model coefficients, and the chi-square test classifying subjects based on the trajectory model's posterior Bayesian probability. The Mplus program was not effective in this application due to its computational demands. The distributions of these tests applied to genes not related to the trait were sensitive to departures from Hardy-Weinberg equilibrium. The likelihood-ratio test statistic was not usable in this application because its distribution was far from the expected asymptotic distributions when applied to markers with no genetic relation to the quantitative trait. The other two tests were satisfactory. Power was still substantial when we used markers near the gene rather than the gene itself. That is, growth mixture modeling may be useful in genome-wide association studies. For markers near the actual gene, there was somewhat greater power for the direct test of the coefficients and lesser power for the posterior Bayesian probability chi-square test

A Model for Transgenerational Imprinting Variation in Complex Traits

Despite the fact that genetic imprinting, i.e., differential expression of the same allele due to its different parental origins, plays a pivotal role in controlling complex traits or diseases, the origin, action and transmission mode of imprinted genes have still remained largely unexplored. We present a new strategy for studying these properties of genetic imprinting with a two-stage reciprocal F mating design, initiated with two contrasting inbred lines. This strategy maps quantitative trait loci that are imprinted (i.e., iQTLs) based on their segregation and transmission across different generations. By incorporating the allelic configuration of an iQTL genotype into a mixture model framework, this strategy provides a path to trace the parental origin of alleles from previous generations. The imprinting effects of iQTLs and their interactions with other traditionally defined genetic effects, expressed in different generations, are estimated and tested by implementing the EM algorithm. The strategy was used to map iQTLs responsible for survival time with four reciprocal F populations and test whether and how the detected iQTLs inherit their imprinting effects into the next generation. The new strategy will provide a tool for quantifying the role of imprinting effects in the creation and maintenance of phenotypic diversity and elucidating a comprehensive picture of the genetic architecture of complex traits and diseases

Increase of Rejection Rate in Case-Control Studies with the Differential Genotyping Error Rates

Genotyping error adversely affects the statistical power of case-control association studies and introduces bias in the estimated parameters when the same error mechanism and probabilities apply to both affected and unaffected individuals; that is, when there is non-differential genotype misclassification. Simulation studies have shown that differential genotype misclassification leads to a rejection rate that is higher than the nominal significance level (type I error rate) for some tests of association.

15q13.3 duplication in two patients with childhood-onset schizophrenia.

We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (α7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc

Effect of low doses of lipopolysaccharide prior to ozone exposure οn bronchoalveolar lavage. Differences between wild type and surfactant protein A-deficient mice

SUMMARY. BACKGROUND: Several aspects of the inflammatory response to a single insult, i.e., exposure to 2 ppm of ozone (O3) for 3 h or 6 h, are less pronounced in surfactant protein A deficient (SP-A -/-) mice (KO) than in wild type mice (WT). It was hypothesized that a mild insult, specifically low doses of lipopolysaccharide (LPS), would adversely affect host defense and differentially potentiate O3-induced injury in WT and KO mice. METHODS: WT and KO mice were treated with different doses of LPS or LPS (2 ng) + O3 (2 ppm) or filtered air (FA) for 3 h, then sacrificed 4 h following exposure (O3, FA) or 20 h after LPS treatment alone. Several endpoints of inflammation were measured in bronchoalveolar lavage (BAL). RESULTS: 1) At 20 h after LPS treatment alone, both WT and KO mice exhibited signs of inflammation, but with differences in the macrophage inflammatory protein 2 (MIP-2) response pattern, total cells (at 0.5 ng LPS) and basal levels of oxidized protein and phospholipids; 2) After LPS + O3, KO compared to WT showed decrease in polymorphonuclear leukocytes (PMNs) and MIP-2 and increase in phospholipids, and after LPS + FA an increase in total cells; 3) WT after LPS + FA showed an increase in SP-A with no further increase after LPS + O3, and an increase in oxidized SP-A dimer following O3 or LPS + O3. CONCLUSIONS: LPS treatment has negative effects on inflammation endpoints in mouse BAL long after exposure and renders KO mice less capable of responding to a second insult. LPS and O3 affect SP-A, quantitatively and qualitatively, respectively. Pneumon 2009; 22(2):131–155

Coordinated Expression of Phosphoinositide Metabolic Genes during Development and Aging of Human Dorsolateral Prefrontal Cortex.

Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade.Gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging.We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years) and Aging (21+ years).We identified three groups of partially overlapping genes in each of the two intervals, with similar intergroup correlations despite marked phenotypic differences between Aging and Development. In each interval, ITPKB, PLCD1, PIK3R3, ISYNA1, IMPA2, INPPL1, PI4KB, and AKT1 are in Group 1, PIK3CB, PTEN, PIK3CA, and IMPA1 in Group 2, and SACM1L, PI3KR4, INPP5A, SYNJ1, and PLCB1 in Group 3. Ten of the genes change expression nonlinearly during Development, suggesting involvement in rapidly changing neuronal, glial and myelination events. Correlated transcription for some gene pairs likely is facilitated by colocalization on the same chromosome band.Stable coordinated gene transcriptional networks regulate brain phosphoinositide metabolic pathways during human Development and Aging

Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease

RATIONALE: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear. OBJECTIVES: We applied Mendelian randomization (MR) analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis). METHODS: We conducted two-sample bidirectional MR to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies (GWAS) conducted on asthma (Ncases=56,167) and GERD (Ncases=71,522). Additionally, we generated instrumental variables (IVs) for atopic dermatitis (AD) from the latest population-level GWAS meta-analysis (Ncases=22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD. MEASUREMENTS AND MAIN RESULTS: Applying three different methods, each method found similar magnitude of causal estimates that were directionally consistent across the sensitivity analyses. Using an inverse-variance weighted method, the largest effect size was detected for asthma predisposition to AD (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.34-1.59), followed by AD to asthma (OR, 1.34; CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; CI, 1.03-1.09), but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; CI, 1.09-1.35) and AD (OR, 1.21; CI, 1.07-1.37). CONCLUSIONS: This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: 1) asthma is a causal risk for AD; and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD