Integrating Genetics and Neuroimaging to study Subtypes of Binge Drinkers

Risky alcohol use is a major health concern among college students, with 40.1% reporting binge drinking (5 or more drinks in one occasion) and 14.4% reporting heavy drinking (binge drinking on 5 or more occasions) in the past month. Risky alcohol use is thought to be the result of a complex interplay between genes, biological processes, and other phenotypic characteristics. Understanding this complex relationship is further complicated by known phenotypic heterogeneity in the development of alcohol use. Developmental studies have suggested two pathways to risky alcohol use, characterized by externalizing and internalizing characteristics, respectively. However, the underlying biological processes that differentiate these pathways are not fully understood. Neuroimaging studies have assessed reward sensitivity, emotion reactivity, and behavioral inhibition using fMRI and separately demonstrate associations in externalizing and internalizing disorders more broadly. In addition, previous genetic studies have found associations between specific polymorphisms and these externalizing and internalizing subtypes. Therefore, we sought further characterize the biological influences on binge drinking subtypes through the following specific aims: 1) determine the genetic relationship between externalizing and internalizing characteristics in binge drinkers, 2) test whether externalizing and internalizing binge drinkers show differences in brain activation in response to tasks measuring emotion reactivity, reward sensitivity, and behavioral inhibition. In order to achieve these aims, we conducted a series of genetic analyses assessing differences in overall SNP-based heritability and specific associated variants between the externalizing and internalizing subtypes. There were a few variants that reached genome-wide significance, the most notable being a cluster of SNPs associated with internalizing characteristics that were located in the RP3AL gene. In a subset of these binge drinking young adults, brain activation was measured on tasks assessing behavioral inhibition, reward sensitivity, and emotion reactivity. We found some preliminary differences with regard to emotion reactivity, that suggest internalizing binge drinkers are more reactive to faces overall but have blunted reaction to sad faces compared to externalizers. These findings provide an initial step to better understanding the underlying biology between the classic externalizing and internalizing alcohol use subtypes, which has the potential to elucidate new subtype specific targets for prevention and intervention

Editorial: Biofabrication and Biopolymeric Materials Innovation for Musculoskeletal Tissue Regeneration

Editorial on the Research Topic Biofabrication and Biopolymeric Materials Innovation for Musculoskeletal Tissue Regeneratio

Patterns of substance use across the first year of college and associated risk factors

Starting college is a major life transition. This study aims to characterize patterns of substance use across a variety of substances across the first year of college and identify associated factors. We used data from the first cohort (N = 2056, 1240 females) of the “Spit for Science” sample, a study of incoming freshmen at a large urban university. Latent transition analysis was applied to alcohol, tobacco, cannabis, and other illicit drug uses measured at the beginning of the fall semester and midway through the spring semester. Covariates across multiple domains – including personality, drinking motivations and expectancy, high school delinquency, peer deviance, stressful events, and symptoms of depression and anxiety – were included to predict the patterns of substance use and transitions between patterns across the first year. At both the fall and spring semesters, we identified three subgroups of participants with patterns of substance use characterized as: (1) use of all four substances; (2) alcohol, tobacco, and cannabis use; and (3) overall low substance use. Patterns of substance use were highly stable across the first year of college: most students maintained their class membership from fall to spring, with just 7% of participants in the initial low substance users transitioning to spring alcohol, tobacco, and cannabis users. Most of the included covariates were predictive of the initial pattern of use, but covariates related to experiences across the first year of college were more predictive of the transition from the low to alcohol, tobacco, and cannabis user groups. Our results suggest that while there is an overall increase in alcohol use across all students, college students largely maintain their patterns of substance use across the first year. Risk factors experienced during the first year may be effective targets for preventing increases in substance use

Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification

Geometric confinement is required for recovery and maintenance of chondrocyte phenotype in alginate

Human articular chondrocytes lose their native phenotype when expanded in traditional monolayer cultures. As a consequence, hydrogel encapsulation has been investigated as a means to maintain the natural phenotype. Alginate has been widely used for cartilage engineering as it has been shown to enable the recovery of a native collagen type II expressing chondrocyte phenotype. This study has evaluated whether the capacity of the materials to maintain/revert the phenotype is due to the composition of the material or the physical entrapment provided by the gel. To achieve this, an alginate “fluid gel” (a shear-thinning structured gel system) was produced of identical chemistry to a traditionally gelled alginate structure. Both were seeded with passaged primary human articular chondrocytes. Chondrocytes in quiescent alginate showed the recovery of the native phenotype and a spherical morphology. Chondrocytes in alginate fluid gel were unable to maintain the recovered phenotype despite having a spherical morphology and were shown to have a lower level of entrapment than those in quiescent alginate. These findings indicate that geometric entrapment is essential for the maintenance of a recovered chondrocyte phenotype in alginate

A genome-wide association study for diabetic nephropathy genes in African Americans

A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD