Is There an Association between Advanced Paternal Age and Endophenotype Deficit Levels in Schizophrenia?

The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects’ birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age–endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia

Common genetic risk of major depression and nicotine dependence: The contribution of antisocial traits in a United States veteran male twin cohort

Many studies that found associations between depression and nicotine dependence have ignored possible shared genetic influences associated with antisocial traits. The present study examined the contribution of genetic and environmental effects associated with conduct disorder (CD) and antisocial personality disorder (ASPD) to the comorbidity of major depression (MD) and nicotine dependence (ND). A telephone diagnostic interview, the Diagnostic Interview Schedule-III-R, was administered to eligible twins from the Vietnam Era Twin (VET) Registry in 1992. Multivariate genetic models were fitted to 3360 middle-aged and predominantly white twin pairs (1868 monozygotic, 1492 dizygotic pairs) of which both members completed the pertinent diagnostic interview sections. Genetic influences on CD accounted for 100%, 68%, and 50% of the total genetic variance in risk for ASPD, MD and ND, respectively. After controlling for genetic influences on CD, the partial genetic correlation between MD and ND was no longer statistically significant. Nonshared environmental contributions to the comorbidity among these disorders were not significant. This study not only demonstrates that the comorbidity between ND and MD is influenced by common genetic risk factors, but also further suggests that the common genetic risk factors overlapped with those for antisocial traits such as CD and ASPD in men

Multimorbidity in bipolar disorder and under-treatment of cardiovascular disease: a cross sectional study

Background: Individuals with serious mental disorders experience poor physical health, especially increased rates of cardiometabolic morbidity and premature morbidity. Recent evidence suggests that individuals with schizophrenia have numerous comorbid physical conditions which may be under-recorded and under-treated but to date very few studies have explored this issue for bipolar disorder. Methods:We conducted a cross-sectional analysis of a dataset of 1,751,841 registered patients within 314 primary-care practices in Scotland, U.K. Bipolar disorder was identified using Read Codes recorded within electronic medical records. Data on 32 common chronic physical conditions were also assessed. Potential prescribing inequalities were evaluated by analyzing prescribing data for coronary heart disease (CHD) and hypertension. Results: Compared to controls, individuals with bipolar disorder were significantly less likely to have no recorded physical conditions (OR 0.59, 95% CI 0.54-0.63) and significantly more likely to have one physical condition (OR 1.27, 95% CI 1.16-1.39), two physical conditions (OR 1.45, 95% CI 1.30-1.62) and three or more physical conditions (OR 1.44, 95% CI 1.30-1.64). People with bipolar disorder also had higher rates of thyroid disorders, chronic kidney disease, chronic pain, chronic obstructive airways disease and diabetes but, surprisingly, lower recorded rates of hypertension and atrial fibrillation. People with bipolar disorder and comorbid CHD or hypertension were significantly more likely to be prescribed no antihypertensive or cholesterol-lowering medications compared to controls, and bipolar individuals with CHD or hypertension were significantly less likely to be on 2 or more antihypertensive agents. Conclusions: Individuals with bipolar disorder are similar to individuals with schizophrenia in having a wide range of comorbid and multiple physical health conditions. They are also less likely than controls to have a primary-care record of cardiovascular conditions such as hypertension and atrial fibrillation. Those with a recorded diagnosis of CHD or hypertension were less likely to be treated with cardiovascular medications and were treated less intensively. This study highlights the high physical healthcare needs of people with bipolar disorder, and provides evidence for a systematic under-recognition and under-treatment of cardiovascular disease in this group

Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

Low cerebrospinal fluid (CSF) Aβ42 levels correlate with increased brain Aβ deposition in Alzheimer’s disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ42 levels than non-carriers. The hypothesis of this investigation was that CSF Aβ42 levels correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ42 levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ42 levels were associated with APOE ε4 status in controls but not in AD patientsA2M regulatory region SNPs were also associated with CSF Aβ42 levels in controls, but not in AD patients, even after adjusting for APOE ε4. These results suggest that genetic variation within the A2M gene influences CSF Aβ42 levels

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk