The
ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we ...have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived
ADH1B*47His allele reaches high frequencies only in western and eastern Asia. To pursue this pattern, we report here new frequency data for 37 populations. Most of our data are from South and Southeast Asia and confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia
after humans had spread across Eurasia.
Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four ...candidate genes for TS (
, and
) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in
and
, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study for response to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited.
The Prevention and Remediation of Insulin Multimorbidity in Europe (PRIME) project aims to investigate the comorbidity of brain and somatic disorders, with a particular focus on metabolic conditions. ...Previous studies carried out as part of this project have provided evidence of genetic factors common to these disorders. This study delves into the cellular aspects of these disorders and their shared biological underpinnings using single-cell data and multi-omics.
In this study, we leveraged the sc-linker framework to integrate single-cell RNA-sequencing (scRNA-seq) data, epigenomic SNP-to-gene maps, and genome-wide association study (GWAS) summary statistics to identify relevant cell types and processes associated with comorbid brain and metabolic disorders, emphasizing insulin multimorbidity. We examined type 2 diabetes (T2D) and several brain disorders in brain tissue, as well as in the liver, which plays a critical role in metabolism, and the colon to explore the association between these tissues and brain/metabolic disorders using single-cell data.
The analysis revealed intriguing associations between type 2 diabetes (T2D) and γ-aminobutyric acid-ergic (GABAergic) inhibitory neurons within the brain. GABAergic neurons, known for their role in neural signaling and inhibitory control, were associated with T2D, suggesting the involvement of neural circuitry dysregulation in insulin-related metabolic disorders. Furthermore, the investigation of liver scRNA-seq data shed light on a specific association between major depressive disorder (MDD) and T2D with dendritic cells in the liver. Dendritic cells are involved in immune response modulation, highlighting the connection between immune dysregulation and T2D multimorbidity. Additionally, the analysis of colon tissue provided evidence linking colonel adipocytes to MDD and T2D, indicating potential shared molecular signatures and underlying biological mechanisms in adipose tissue.
The findings contribute to understanding the cellular mechanisms underlying brain-metabolic disorder comorbidity, particularly in T2D. By integrating scRNA-seq, epigenomic information, and GWAS summary statistics, GABAergic inhibitory neurons were identified as potential cellular components of T2D within the brain. Furthermore, the study suggests a disease-specific involvement of dendritic cells in both MDD and T2D in the liver, emphasizing the contribution of immune-related processes to metabolic dysfunction. Additionally, the adipose-related results highlight the significance of lipid metabolism in the shared biology of T2D and brain disorders. The integration of multi-omics data through the sc-linker framework provides valuable insights into the shared biology of brain and metabolic disorders, paving the way for targeted therapeutic interventions. The results highlight the potential importance of neural circuitry dysregulation, immune-related processes, and lipid metabolism in the pathogenesis and comorbidity of brain and metabolic disorders. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847879.
The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have ...identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.1
The PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe) project aims to investigate the correlation between insulin-related somatic disorders and brain disorders. Previous research ...within the project has demonstrated shared genetic factors among these disorders. Besides genetic factors, environmental factors may also contribute to their development. Cells can respond and adapt to environmental changes by modifying their gene expression, a process influenced by epigenetic mechanisms like chromatin remodeling.
We utilized the H-MAGMA software to conduct gene-based analysis incorporating chromatin interaction profiles (Hi-C data) from human brain tissues. This approach allowed us to extract valuable biological insights from genome-wide association study (GWAS) summary statistics. Epigenetic analyses were performed on 21 pairs of three insulin-related somatic diseases and seven neuropsychiatric disorders using cross-disorder GWAS summary statistics and chromatin interaction profiles from human brain tissues.
Our analysis revealed significant gene-based associations for all pairs of disorders. We identified several genes that were shared across multiple disorders, which are known to have relevant neurobiological functions and have previously been associated with the investigated disorders. Notable genes among the frequently overlapping ones include RHOA, IHO1, NDUFAF3, PKHD1, CCDC71, TMEM219, AMT, ARIH2, NPIPB11, QRICH1, TAOK2, and BANK1, showing significant associations across various disorder pairs. RHOA, CCDC71, and TAOK2 have previously been linked to both somatic insulin-related disorders and neurodevelopmental disorders. Subsequently, we performed a Gene Ontology analysis on genes that were significant in at least three disorder pairs in our cross-disorder analyses (n=420 genes). The Gene Ontology analysis indicated enrichment in three major biological process domains ("epigenetics," immune system, and mitochondrial organization), as well as a few minor domains. These findings suggest the potential involvement of these processes in the multimorbidity between somatic and brain insulin-related disorders. In the ``epigenetics'' domain specifically, we identified genes associated with covalent chromatin modifications, histone modifications, lysine acetylation, and various protein modifications. Importantly, the enrichment of genes in the epigenetics-related domain is independent of the original use of the H-MAGMA method.
Our findings provide valuable insights into the intricate relationship between somatic and brain insulin-related disorders, emphasizing the significance of epigenetic factors. The results support previous findings within the PRIME project and contribute to the understanding of shared genetic and environmental factors underlying these disorders. Further research is necessary to validate these findings and explore the mechanisms behind the comorbidity observed between somatic and brain insulin-related disorders. The insights gained from this study have the potential to aid in the development of targeted interventions and personalized medicine approaches for individuals with co-occurring somatic and psychiatric disorders.
A common genetic basis of various substance and behavioral addictions has long been suggested considering the rate of co-occurrences and the overlaps in psychological and molecular mechanisms. The ...goal of the current study is to investigate possible genetic overlaps between different types of substance-related, addictive and compulsive behaviors conducted as part of the Psychological and Genetic Factors of Addictions (PGA) study. The genetic analysis of both substance and behavioral addictions was conducted within the same cohort of 3003 Hungarian young adults. Participants were assessed for a wide range of potentially addictive substances (nicotine, alcohol, cannabis, and other drugs) and potentially addictive behaviors (internet use, gaming, social networking site use, gambling, exercising, hair-pulling and eating) in order to investigate possible shared genetic factors utilizing the large sample of the PGA study. A Genetic Addiction Risk Score (GARS) was also calculated for the participants based on a set of 11 genetic polymorphisms in order to estimate addiction vulnerability risk scores for possible future prevention strategy as well as personalized pharmacological and non-pharmacological therapy.
The genetic association analysis included 32 single-nucleotide polymorphisms (SNPs) selected from earlier GWAS and candidate gene association studies in the literature in order to best represent the expected distribution pattern of the various phenotypes assessed in the sample. The genotyping was carried out by the The QuantStudio™ 12K Flex OpenArray® System, fluorescent intensities were evaluated by the QuantStudio 12K Flex Software and the Thermo Fisher Cloud service. The genetic association analysis was conducted applying an allele-wise design. The phenotype measures were assessed using multiple questionnaires. The GARS score was calculated based on the risk scores of 11 genetic variants (SNPs and VNTRs).
The statistical analyses revealed 29 nominally significant genetic associations, from which nine survived FDRbl correction for multiple testing. Four of the nine significant associations were observed between the FOXN3 rs759364 SNP and certain potentially addictive behavioral traits: frequency of alcohol consumption and mean scores of scales assessing internet addiction, gaming disorder and exercise addiction. Significant associations were found between GDNF rs1549250, rs2973033, CNR1 rs806380 and DRD2/ANKK1 rs1800497 variants and the ‘lifetime other drugs’ variable. The GARS score was calculated for each participants and significant score differences have been identified between different subgroups of the cohort.
The results indicate a pleiotropic effect, ie. that certain genetic factors may contribute to multiple forms of addiction. Based on the presented results, rs759364 of FOXN3 is shown to constitute genetic risk for increased alcohol consumption, internet use, gaming and exercise, while rs1549250, rs2973033 of GDNF may be non-specific genetic risk factors for various types of addictive behaviors. The GARS scoring is a useful tool to evaluate the individual susceptibility for substance use disorders. Future studies should examine functional correlates and potential mechanisms underlying these relationships.
Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism ...spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.
Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).
As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.
Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
Psychiatric genetic research has exploded in search of polygenic risk factors over the past decade, but because of the complexity and heterogeneity of mental illnesses, using the current ...understanding of the genome has not reached the conclusion of finding a cause for psychiatric disorders. Obsessive-compulsive disorder is a relatively common and often debilitating neuropsychiatric disorder that has not been the primary focus in psychiatric research. Clinicians and researchers who have dedicated to investigate the genetics of obsessive-compulsive disorder have detected a strong genetic involvement. This review will provide an update and a new perspective on the current understanding of the genetics of obsessive-compulsive disorder, which includes epidemiological data, family and twins studies, candidate gene studies, genome-wide association studies, copy-number variants, imaging genetics, epigenetics, and gene–environment interaction.
Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson’s disease, often leads to the development of abnormal involuntary movements (AIMs), which ...represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets.
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