Metabolic Syndrome: An Overview on Its Genetic Associations and Gene-Diet Interactions.

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias and whose inter-related occurrence may increase the odds of developing type 2 diabetes and cardiovascular diseases. MetS has become one of the most studied conditions, nevertheless, due to its complex etiology, this has not been fully elucidated. Recent evidence describes that both genetic and environmental factors play an important role on its development. With the advent of genomic-wide association studies, single nucleotide polymorphisms (SNPs) have gained special importance. In this review, we present an update of the genetics surrounding MetS as a single entity as well as its corresponding risk factors, considering SNPs and gene-diet interactions related to cardiometabolic markers. In this study, we focus on the conceptual aspects, diagnostic criteria, as well as the role of genetics, particularly on SNPs and polygenic risk scores (PRS) for interindividual analysis. In addition, this review highlights future perspectives of personalized nutrition with regard to the approach of MetS and how individualized multiomics approaches could improve the current outlook.

Systems-Level Analysis of Genetic Variants Reveals Functional and Spatiotemporal Context in Treatment-resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) occurs in one-third of the patients, but the molecular determinants of poor antipsychotic response remain unclear. We compared genetic data of patients with TRS (n = 63) with non-TRS (n = 111) by polygenic risk scores (PRS) calculated by PRSice software using PGC2_SCZ (Psychiatric Genomics Consortium - Schizophrenia) data. TRS criteria followed the International Psychopharmacology Algorithm Project SCZ algorithm. Statistical clustering and functional enrichment analyses of genes harboring TRS-linked variants were performed. Individuals on the top three deciles of schizophrenia PRS distribution exhibited higher odds of being refractory to antipsychotics than those on the bottom three deciles. Clusters of interacting variant-harboring genes were identified among the association signals. They are upregulated in the dorsolateral prefrontal, orbitofrontal, temporal, and inferior parietal areas during adolescence and early adulthood. Similar gene modules were found using transcriptional data from the same brain regions in individuals with schizophrenia. Genes were enriched among markers of cortical interneurons and somatosensory pyramidal cells. Finally, the enrichment of the clustered genes in drug-response expression signatures revealed compounds that could be employed to identify novel antipsychotic targets. In conclusion, we identified variant-harboring genes that may predispose SCZ patients to poor antipsychotic response and found statistically enriched clusters which provided functional and spatiotemporal context for TRS, suggesting that genotypic variation may converge to biological alterations at the interplay between actin dynamics and synaptic organization.

Association between Polygenic Risk Scores for ADHD and Asthma: A Birth Cohort Investigation.

OBJECTIVE: Shared genetic mechanisms have been hypothesized to explain the comorbidity between ADHD and asthma. To evaluate their genetic overlap, we relied on data from the 1982 Pelotas birth cohort to test the association between polygenic risk scores (PRSs) for ADHD (ADHD-PRSs) and asthma, and PRSs for asthma (asthma-PRSs) and ADHD. METHOD: We analyzed data collected at birth, 2, 22, and 30 years from 3,574 individuals. RESULTS: Subjects with ADHD had increased risk of having asthma (OR 1.92, 95% CI 1.01-3.66). The association was stronger for females. Our results showed no evidence of association between ADHD-PRSs and asthma or asthma-PRSs and ADHD. However, an exploratory analysis suggested that adult ADHD might be genetically associated with asthma. CONCLUSION: Our results do not support a shared genetic background between both conditions. Findings should be viewed in light of important limitations, particularly the sample size and the self-reported asthma diagnosis. Studies in larger datasets are required to better explore the genetic overlap between adult ADHD and asthma.

Suicidal ideation and planning among Mexican adolescents are associated with depression polygenic risk scores.

Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA individuals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N = 1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N = 437, 20-25 years, 63% women). At both assessments, individuals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.

Integrative Genomic-Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis.

Clozapine (CLZ) is the only antipsychotic drug that has been proven to be effective in patients with refractory psychosis, but it has also been proposed as an effective mood stabilizer; however, the complex mechanisms of action of CLZ are not yet fully known. To find predictors of CLZ-associated phenotypes (i.e., the metabolic ratio, dosage, and response), we explore the genomic and epigenomic characteristics of 44 patients with refractory psychosis who receive CLZ treatment based on the integration of polygenic risk score (PRS) analyses in simultaneous methylome profiles. Surprisingly, the PRS for bipolar disorder (BD-PRS) was associated with the CLZ metabolic ratio (pseudo-R2 = 0.2080, adjusted p-value = 0.0189). To better explain our findings in a biological context, we assess the protein-protein interactions between gene products with high impact variants in the top enriched pathways and those exhibiting differentially methylated sites. The GABAergic synapse pathway was found to be enriched in BD-PRS and was associated with the CLZ metabolic ratio. Such interplay supports the use of CLZ as a mood stabilizer and not just as an antipsychotic. Future studies with larger sample sizes should be pursued to confirm the findings of this study.

EXPLORATORY ANALYSIS OF POLYGENIC RISK SCORES FOR PSYCHIATRIC DISORDERS: APPLIED TO DUAL DIAGNOSIS.

BACKGROUND: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). METHODS: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. RESULTS: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. CONCLUSIONS: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.

Exploratory analysis of polygenic risk scores for psychiatric disorders: Applied to dual diagnosis

Background Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.

Heterotypic trajectories of dimensional psychopathology across the lifespan: the case of youth-onset attention deficit/hyperactivity disorder.

BACKGROUND: Recent studies have demonstrated the existence of a distinct late-onset attention deficit/hyperactivity disorder (ADHD) trajectory. Our objective is to test if there are distinct ADHD trajectories regarding age of onset from childhood to adolescence and to compare clinical manifestations, cognitive functions and genetic risk for ADHD among distinct longitudinal groups. METHOD: Nine hundred and twenty four children and adolescents from the community participated in the study. We compared clinical, cognitive features and genetic risk among four groups of participants: (a) childhood-limited, (b) youth-onset, (c) childhood-onset with youth persistence, and (d) community comparisons without ADHD. Symptomatic and diagnostic assessments were performed using the Development and Well-Being Behavior Assessment, the Strengths and Difficulties Questionnaire, and the Child Behavior Checklist. Cognitive functions were measured using a battery of standardized tests. Genetic risk for ADHD was calculating using summary statistics from the Psychiatric Genomics Consortium. RESULTS: Half of the adolescents (52%) with ADHD had their symptom onset in adolescence. The impairment level of this group in adolescence is similar to the persistent group. Despite not having ADHD, the youth-onset group already presented in childhood more symptoms from other domains of psychopathology, higher shared variance in psychiatric symptomatology (p-factor), school impairment, and executive dysfunctions than community comparisons. Furthermore, the youth-onset group presented lower levels of genetic risk for ADHD compared to other cases. CONCLUSIONS: A significant proportion of adolescents with ADHD were youth-onset cases and presented similar impairment levels as those cases with early-onset ADHD. The presence of cognitive impairments and higher levels of clinical symptoms in the youth-onset group already at childhood speaks in favor of a heterotypic trajectory of psychopathology suggesting that youth-onset ADHD might be an artificial consequence of categorizing dimensional psychopathology into discrete diagnostic groups.