Genetics of Alcoholism Edenberg, Howard J.; Gelernter, Joel; Agrawal, Arpana
Current psychiatry reports,
04/2019, Letnik:
21, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
We review the search for genetic variants that affect the risk for alcohol dependence and alcohol consumption.
Recent Findings
Variations in genes affecting alcohol metabolism (
...ADH1B
,
ALDH2
) are protective against both alcohol dependence and excessive consumption, but different variants are found in different populations. There are different patterns of risk variants for alcohol dependence vs. consumption. Variants for alcohol dependence, but not consumption, are associated with risk for other psychiatric illnesses.
Summary
ADH1B
and
ALDH2
strongly affect both consumption and dependence. Variations in many other genes affect both consumption and dependence—or one or the other of these traits—but individual effect sizes are small. Evidence for other specific genes that affect dependence is not yet strong. Most current knowledge derives from studies of European-ancestry populations, and large studies of carefully phenotyped subjects from different populations are needed to understand the genetic contributions to alcohol consumption and alcohol use disorders.
Hydrogels have emerged as a versatile and promising class of materials in the field of 3D printing, offering unique properties suitable for various applications. This review delves into the ...intersection of hydrogels and 3D printing, exploring current research, technological advancements, and future directions. It starts with an overview of hydrogel basics, including composition and properties, and details various hydrogel materials used in 3D printing. The review explores diverse 3D printing methods for hydrogels, discussing their advantages and limitations. It emphasizes the integration of 3D-printed hydrogels in biomedical engineering, showcasing its role in tissue engineering, regenerative medicine, and drug delivery. Beyond healthcare, it also examines their applications in the food, cosmetics, and electronics industries. Challenges like resolution limitations and scalability are addressed. The review predicts future trends in material development, printing techniques, and novel applications.
Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is ...not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.
Abstract
Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week ...(DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces
SPI1
mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies
MAPT
as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.
Abstract Imaging genetics and genomics research has begun to provide insight into the molecular and genetic architecture of neural phenotypes and the neural mechanisms through which genetic risk for ...psychopathology may emerge. As it approaches its third decade, imaging genetics is confronted by many challenges including the proliferation of studies using small sample sizes and diverse designs, limited replication, problems with harmonization of neural phenotypes for meta-analysis, unclear mechanisms, and evidence that effect sizes may be more modest than originally posited, with increasing evidence of polygenicity. These concerns have encouraged the field to grow in many new directions including the development of consortia and large scale data collection projects as well as the use of novel methods (e.g., polygenic approaches, machine learning), which enhance the quality of imaging genetic studies, but also introduce new challenges. Here, we critically review progress in imaging genetics and offer suggestions and highlight potential pitfalls of novel approaches. Ultimately, the strength of imaging genetics and genomics lies in its translational and integrative potential with other research approaches (e.g., non-human animal models, psychiatric genetics, pharmacologic challenge) to elucidate brain-based pathways that give rise to the vast individual differences in behavior as well as risk for psychopathology.
Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not ...yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study's findings suggest that genetic differences in hippocampal longitudinal axis structure can be detected in individual differences in gray matter volume in population-level research designs.
Genome-wide association studies and other discovery genetics methods provide a means to identify previously unknown biological mechanisms underlying behavioral disorders that may point to new ...therapeutic avenues, augment diagnostic tools, and yield a deeper understanding of the biology of psychiatric conditions. Recent advances in psychiatric genetics have been made possible through large-scale collaborative efforts. These studies have begun to unearth many novel genetic variants associated with psychiatric disorders and behavioral traits in human populations. Significant challenges remain in characterizing the resulting disease-associated genetic variants and prioritizing functional follow-up to make them useful for mechanistic understanding and development of therapeutics. Model organism research has generated extensive genomic data that can provide insight into the neurobiological mechanisms of variant action, but a cohesive effort must be made to establish which aspects of the biological modulation of behavioral traits are evolutionarily conserved across species. Scalable computing, new data integration strategies, and advanced analysis methods outlined in this review provide a framework to efficiently harness model organism data in support of clinically relevant psychiatric phenotypes.
Associations between brain structure and problematic alcohol use may reflect alcohol-induced toxicity and/or preexisting risk. Here, we applied a latent causal variable approach to genome-wide ...association study summary statistics of problematic alcohol use (n = 435,563) and magnetic resonance imaging-derived brain structure phenotypes (e.g., cortical volume, cortical thickness, white matter volume; ns ranging from 17,706 to 51,665) to test whether variability in brain structure may plausibly contribute to problematic alcohol use and/or whether problematic alcohol use influences brain structure. After correction for multiple testing within each modality, we find evidence that greater volume of the pars opercularis, greater thickness of the cuneus, and lower volume of the basal forebrain may plausibly contribute to problematic alcohol use. All other nominally-significant associations identify brain structure as a potential causal contributor to problematic alcohol use; there was no evidence suggesting that problematic alcohol use may cause differences in brain structure. Collectively, these results challenge common interpretations that associations between alcohol use and brain structure reflect consequences of alcohol, instead supporting emerging work suggesting that brain structure may reflect a predispositional risk factor for alcohol involvement.
Excessive substance use and substance use disorders (SUDs) are common, serious and relapsing medical conditions. They frequently co-occur with other diseases that are leading contributors to ...disability worldwide. While heavy substance use may potentiate the course of some of these illnesses, there is accumulating evidence suggesting common genetic architectures. In this narrative review, we focus on four heritable medical conditions - cardiometabolic disease, chronic pain, depression and COVID-19, which are commonly overlapping with, but not necessarily a direct consequence of, SUDs. We find persuasive evidence of underlying genetic liability that predisposes to both SUDs and chronic pain, depression, and COVID-19. For cardiometabolic disease, there is greater support for a potential causal influence of problematic substance use. Our review encourages de-stigmatization of SUDs and the assessment of substance use in clinical settings. We assert that identifying shared pathways of risk has high translational potential, allowing tailoring of treatments for multiple medical conditions.
SSR acknowledges T29KT0526, T32IR5226 and DP1DA054394; RLK acknowledges AA028292; AA acknowledges DA054869 & K02DA032573. The funders had no role in the conceptualization or writing of the paper.
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