Genetic Risks to Nicotine Dependence Predict Negative Mood and Affect in Current Non-Smokers

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively) and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence

Genetic Risks to Nicotine Dependence Predict Negative Mood and Affect in Current Non-Smokers

Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug and its effects on human psychology are largely under-investigated in genetic studies. In this study, we recruited 208 current non-smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively) and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence

Schizophrenia Gene Networks and Pathways and Their Applications for Novel Candidate Gene Selection

Background Schizophrenia (SZ) is a heritable, complex mental disorder. We have seen limited success in finding causal genes for schizophrenia from numerous conventional studies. Protein interaction network and pathway-based analysis may provide us an alternative and effective approach to investigating the molecular mechanisms of schizophrenia. Methodology/Principal Findings We selected a list of schizophrenia candidate genes (SZGenes) using a multi-dimensional evidence-based approach. The global network properties of proteins encoded by these SZGenes were explored in the context of the human protein interactome while local network properties were investigated by comparing SZ-specific and cancer-specific networks that were extracted from the human interactome. Relative to cancer genes, we observed that SZGenes tend to have an intermediate degree and an intermediate efficiency on a perturbation spreading throughout the human interactome. This suggested that schizophrenia might have different pathological mechanisms from cancer even though both are complex diseases. We conducted pathway analysis using Ingenuity System and constructed the first schizophrenia molecular network (SMN) based on protein interaction networks, pathways and literature survey. We identified 24 pathways overrepresented in SZGenes and examined their interactions and crosstalk. We observed that these pathways were related to neurodevelopment, immune system, and retinoic X receptor (RXR). Our examination of SMN revealed that schizophrenia is a dynamic process caused by dysregulation of the multiple pathways. Finally, we applied the network/pathway approach to identify novel candidate genes, some of which could be verified by experiments. Conclusions/Significance This study provides the first comprehensive review of the network and pathway characteristics of schizophrenia candidate genes. Our preliminary results suggest that this systems biology approach might prove promising for selection of candidate genes for complex diseases. Our findings have important implications for the molecular mechanisms for schizophrenia and, potentially, other psychiatric disorders

Polygenic Risk Scores for Subtyping of Schizophrenia

Schizophrenia is a complex disorder with many comorbid conditions. In this study, we used polygenic risk scores (PRSs) from schizophrenia and comorbid traits to explore consistent cluster structure in schizophrenia patients. With 10 comorbid traits, we found a stable 4-cluster structure in two datasets (MGS and SSCCS). When the same traits and parameters were applied for the patients in a clinical trial of antipsychotics, the CATIE study, a 5-cluster structure was observed. One of the 4 clusters found in the MGS and SSCCS was further split into two clusters in CATIE, while the other 3 clusters remained unchanged. For the 5 CATIE clusters, we evaluated their association with the changes of clinical symptoms, neurocognitive functions, and laboratory tests between the enrollment baseline and the end of Phase I trial. Class I was found responsive to treatment, with significant reduction for the total, positive, and negative symptoms (p=0.0001, 0.0099, and 0.0028, respectively), and improvement for cognitive functions (VIGILANCE, p=0.0099; PROCESSING SPEED, p=0.0006; WORKING MEMORY, p=0.0023; and REASONING, p=0.0015). Class II had modest reduction of positive symptoms (p=0.0492) and better PROCESSING SPEED (p=0.0071). Class IV had a specific reduction of negative symptoms (p=0.0111) and modest cognitive improvement for all tested domains. Interestingly, Class IV was also associated with decreased lymphocyte counts and increased neutrophil counts, an indication of ongoing inflammation or immune dysfunction. In contrast, Classes III and V showed no symptom reduction but a higher level of phosphorus. Overall, our results suggest that PRSs from schizophrenia and comorbid traits can be utilized to classify patients into subtypes with distinctive clinical features. This genetic susceptibility based subtyping may be useful to facilitate more effective treatment and outcome prediction

Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects

To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina

Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes

Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case–control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations

ACSL6 Is Associated with the Number of Cigarettes Smoked and Its Expression Is Altered by Chronic Nicotine Exposure

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n\u3e16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression ofACSL6 requires nicotinic receptor activation. These findings suggest that variations in theACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions

A Frameshift Variant in the CHST9 Gene Identified by Family-Based Whole Genome Sequencing Is Associated with Schizophrenia in Chinese Population

Recent studies imply that rare variants contribute to the risk of schizophrenia, however, the exact variants or genes responsible for this condition are largely unknown. In this study, we conducted whole genome sequencing (WGS) of 20 Chinese families. Each family consisted of at least two affected siblings diagnosed with schizophrenia and at least one unaffected sibling. We examined functional variants that were found in affected sibling(s) but not in unaffected sibling(s) within a family. Matching this criterion, a frameshift heterozygous deletion of CA (–/CA) at chromosome 18:24722722, also referred to as rs752084147, in the Carbohydrate Sulfotransferase 9 (CHST9) gene, was detected in two families. This deletion was confirmed by PCR-based Sanger sequencing. With the observed frequency of 0.00076 in Han Chinese population, we performed both case-control and family-based analyses to evaluate its association with schizophrenia. In the case-control analyses, Chi-square test P-value was 6.80e-12 and the P-value was 0.0008 after one million simulations. In family-based segregation analyses, segregation P-value was 7.72e-7 and simulated P-value was 5.70e-6. For both the case-control and family-based analyses, the CA deletion was significantly associated with schizophrenia in the Chinese population. Further investigation of this gene is warranted in the development of schizophrenia by utilizing larger and more ethnically diverse samples

CNx-modified Fe3O4 as Pt nanoparticle support for the oxygen reduction reaction

A novel electrocatalyst support material, nitrogendoped carbon (CNx)-modified Fe3O4 (Fe3O4-CNx), was synthesized through carbonizing a polypyrrole-Fe3O4 hybridized precursor. Subsequently, Fe3O4-CNx-supported Pt (Pt/Fe3O4-CNx) nanocomposites were prepared by reducing Pt precursor in ethylene glycol solution and evaluated for the oxygen reduction reaction (ORR). The Pt/Fe3O4-CNx catalysts were characterized by X-ray diffraction, Raman spectra, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The electrocatalytic activity and stability of the as-prepared electrocatalysts toward ORR were studied by cyclic voltammetry and steady-state polarization measurements. The results showed that Pt/ Fe3O4-CNx catalysts exhibited superior catalytic performance for ORR to the conventional Pt/C and Pt/C-CNx catalysts.Web of Scienc

Population-specific coding variant underlies genome-wide association with adiponectin level

Adiponectin is a protein hormone that can affect major metabolic processes including glucose regulation and fat metabolism. Our previous genome-wide association (GWA) study of circulating plasma adiponectin levels in Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) detected a 100 kb two-SNP haplotype at KNG1–ADIPOQ associated with reduced adiponectin (frequency = 0.050, P = 1.8 × 10−25). Subsequent genotyping of CLHNS young adult offspring detected an uncommon variant [minor allele frequency (MAF) = 0.025] located ∼800 kb from ADIPOQ that showed strong association with lower adiponectin levels (P = 2.7 × 10−15, n = 1695) and tagged a subset of KNG1–ADIPOQ haplotype carriers with even lower adiponectin levels. Sequencing of the ADIPOQ-coding region detected variant R221S (MAF = 0.015, P = 2.9 × 10−69), which explained 17.1% of the variance in adiponectin levels and largely accounted for the initial GWA signal in Filipinos. R221S was not present in 12 514 Europeans with previously sequenced exons. To explore the mechanism of this substitution, we re-measured adiponectin level in 20 R221S offspring carriers and 20 non-carriers using two alternative antibodies and determined that the presence of R221S resulted in artificially low quantification of adiponectin level using the original immunoassay. These data provide an example of an uncommon variant responsible for a GWA signal and demonstrate that genetic associations with phenotypes measured by antibody-based quantification methods can be affected by uncommon coding SNPs residing in the antibody target region