Background

Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association.

Methods

We analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system.

Results

MCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating.

Conclusions

Our study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia.

Alcohol is a widely consumed substance in the United States, however its effect on aging remains understudied. In this study of young adults, we examined whether cumulative alcohol consumption, i.e., alcohol years of beer, liquor, wine, and total alcohol, and recent binge drinking, were associated with four measures of age-related epigenetic changes via blood DNA methylation. A random subset of study participants in the Coronary Artery Risk Development in Young Adults Study underwent DNA methylation profiling using the Illumina MethylationEPIC Beadchip. Participants with alcohol consumption and methylation data at examination years 15 (n = 1,030) and 20 (n = 945) were included. Liquor and total alcohol consumption were associated with a 0.31-year (P = 0.002) and a 0.12-year (P = 0.013) greater GrimAge acceleration (GAA) per additional five alcohol years, while beer and wine consumption observed marginal (P = 0.075) and no associations (P = 0.359) with GAA, respectively. Any recent binge drinking and the number of days of binge drinking were associated with a 1.38-year (P < 0.001) and a 0.15-year (P < 0.001) higher GAA, respectively. We observed statistical interactions between cumulative beer (P < 0.001) and total alcohol (P = 0.004) consumption with chronological age, with younger participants exhibiting a higher average in GAA compared to older participants. No associations were observed with the other measures of epigenetic aging. These results suggest cumulative liquor and total alcohol consumption and recent binge drinking may alter age-related epigenetic changes as captured by GAA. With the increasing aging population and widespread consumption of alcohol, these findings may have potential implications for lifestyle modification to promote healthy aging.

STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control-a process critical for all cancer types-we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR=1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR=1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value=0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value<0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.