Gene - maltreatment interplay in adult ADHD symptoms: main role of a gene-environment correlation effect in a Brazilian population longitudinal study.

Childhood maltreatment correlates with attention-deficit/hyperactivity disorder (ADHD) in previous research. The interaction between ADHD genetic predisposition and maltreatment's impact on ADHD symptom risk remains unclear. We aimed to elucidate this relationship by examining the interplay between a polygenic score for ADHD (ADHD-PGS) and childhood maltreatment in predicting ADHD symptoms during young adulthood. Using data from the 2004 Pelotas (Brazil) birth cohort comprising 4231 participants, we analyzed gene-environment interaction (GxE) and correlation (rGE). We further explored rGE mechanisms through mediation models. ADHD symptoms were assessed at age 18 via self-report (Adult Self Report Scale - ASRS) and mother-reports (Strength and Difficulties Questionnaire - SDQ). The ADHD-PGS was derived from published ADHD GWAS meta-analysis. Physical and psychological child maltreatment was gauged using the Parent-Child Conflict Tactics Scale (CTSPC) at ages 6 and 11, with a mean score utilized as a variable. The ADHD-PGS exhibited associations with ADHD symptoms on both ASRS (ß = 0.53; 95% CI: 0.03; 1.03, p = 0.036), and SDQ (ß = 0.20; 95% CI: 0.08; 0.32, p = 0.001) scales. The total mean maltreatment score was associated with ADHD symptoms using both scales [(ßASRS = 0.51; 95% CI: 0.26;0.77) and (ßSDQ = 0.24; 95% CI: 0.18;0.29)]. The ADHD-PGS was associated with total mean maltreatment scores (ß = 0.09; 95% CI: 0.01; 0.17; p = 0.030). Approximately 47% of the total effect of ADHD-PGS on maltreatment was mediated by ADHD symptoms at age 6. No evidence supported gene-environment interaction in predicting ADHD symptoms. Our findings underscore the significant roles of genetics and childhood maltreatment as predictors for ADHD symptoms in adulthood, while also indicating a potential evocative mechanism through gene-environment correlation.

Can miRNA Indicate Risk of Illness after Continuous Exposure to M. tuberculosis?

The role of regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humans and it is still a challenge to prevent and treat. Control of the infection, as well as its diagnosis, are still complex and current treatments used are linked to several side effects. This study aimed to identify possible biomarkers for tuberculosis by applying NGS techniques to obtain global miRNA expression profiles from 22 blood samples of infected patients with tuberculosis (n = 9), their respective healthy physicians (n = 6) and external healthy individuals as controls (n = 7). Samples were run through a pipeline consisting of differential expression, target genes, gene set enrichment and miRNA-gene network analyses. We observed 153 altered miRNAs, among which only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results indicate that miRNAs may be involved in immune modulation by regulating gene expression in cells of the immune system. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis.

Blood groups in Native Americans: a look beyond ABO and Rh.

The study presents comparisons between blood group frequencies beyond ABO and Rh blood systems in Native American populations and previously published data from Brazilian blood donors. The frequencies of Diego (c.2561C>T, rs2285644), Kell (c.578C>T, rs8176058), Duffy (c.125A>G, rs12075, c.1-67T>C, rs2814778) and Kidd (c.838A>G, rs1058396) variants in Kaingang (n=72) and Guarani (n=234) populations from Brazil (1990-2000) were obtained and compared with data from these populations sampled during the 1960s and with individuals of different Brazilian regions. Data showed high frequencies of DI*01 and FY*01 alleles: 11.8% and 57.6% in Kaingang and 6.8% and 75.7% in Guarani groups, respectively. The main results indicated: (1) reduction in genetic distance over time of Kaingang and Guarani in relation to other Brazilian populations is suggestive of ongoing admixture; (2) significant differences in some frequencies of blood group markers (especially Diego, Kidd and Duffy) in relation to Native Americans and individuals from different geographical regions of Brazil. Our study shows that the frequency of red blood cell polymorphisms in two Native American groups is very different from that of blood donors, when we evaluated blood groups different from ABO and Rh systems, suggesting that a better ethnic characterization of blood unit receptors is necessary.

Assessing causality in the association between attention-deficit/hyperactivity disorder and obesity: a Mendelian randomization study.

BACKGROUND/OBJECTIVES: Attention-deficit hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in childhood and adolescence, is associated with obesity in observational studies. However, it is unclear whether ADHD contributes to, results from or is merely correlated with obesity. This study evaluates the presence and direction of a causal effect between ADHD and obesity. SUBJECTS/METHODS: We performed a bidirectional two-sample Mendelian randomization using summary data from consortia of genome-wide association studies to investigate if ADHD (N = 55,374) has a causal effect on body mass index (BMI) in childhood (N = 35,668) and adulthood (N = 322,154-500,000), and vice-versa. The main analysis was performed using the inverse variance weighted (IVW) method. As sensitivity analyses, we used other Mendelian randomization methods that are more robust to horizontal pleiotropy (i.e., MR-Egger, weighted mode, and penalized weighted median estimators), as well as stratified the analysis by the putative mechanisms of genetic instruments (i.e., pathways involved or not in neurological processes). RESULTS: The IVW method indicated a positive causal effect of BMI on ADHD: ß = 0.324 (95% CI 0.198 to 0.449, p < 0.001; expressed as change in ln(odds ratio) of ADHD per each additional SD unit of BMI). IVW estimates were directionally consistent with other methods. On the other hand, we did not find consistent evidence for a causal effect of ADHD genetic liability on BMI. CONCLUSIONS: The results suggested that higher BMI increases the risk of developing ADHD, but not the other way around.

Variability of innate immune system genes in Native American populations-relationship with history and epidemiology.

OBJECTIVES: The immune system of a host, defending him/her against invading pathogens, has two main subsystems: innate immunity and acquired immunity. There are several evidences showing that Native American populations are immunologically different from non-Native populations. Our aim was to describe the variability of innate immune system genes in Native American populations. MATERIALS AND METHODS: We investigated heterozygozities and patterns of population differentiation (FST ) of 14 polymorphisms related to the innate immune response in five Native American populations (Aché, Guarani-Kaiowá, Guarani-Ñandeva, Kaingang, and Xavante) and the results were compared with the three major world population data (YRI, CEU, and CHB) available at the 1,000 genomes database. RESULTS: Mean heterozygosities ranged between 0.241 ± 0.057 (Aché) and 0.343 ± 0.033 (Kaingang), but no significant differences were observed (Friedman test, P = 0.197). Mean heterozygosities were also not significantly different when Amerindians were pooled and compared with the 1000 genomes populations (Friedman test, P = 0.506). When the Native American populations were grouped as Amerindians, a significantly higher FST value (0.194) was observed between the Amerindian and African populations. The Ewens-Watterson neutrality test showed that these markers are not under strong selective pressure. DISCUSSION: Native American populations present similar levels of heterozygosity as those of other continents, but are different from Africans in the frequency of polymorphisms of innate immune genes. This higher differentiation is probably due to demographic processes that occurred during the out-of-Africa event.

Influence of CYP19A1 polymorphisms on the treatment of breast cancer with aromatase inhibitors: a systematic review and meta-analysis.

BACKGROUND: Many clinical trials have shown the efficacy of aromatase inhibitors (AIs) in the management of breast cancer (BC). There is growing evidence that CYP19A1 single-nucleotide polymorphisms (SNPs) are associated with clinical response (CR) and adverse effects (AEs) among BC patients treated with AIs. The aim of this study was to analyze the association between CYP19A1 polymorphisms and AI treatment in BC patients. METHODS: A systematic review was performed in MEDLINE, EMBASE, and LILACS. A meta-analysis was conducted to compare the association between CYP19A1 variants and treatment response among BC patients. RESULTS: A total of 12 studies were included in the final analysis. There was significant variation among the populations studied and the SNPs and outcomes investigated. A meta-analysis was only possible for the evaluation of SNP rs4646 vs. the wild-type variant with respect to time to progression (TTP) among metastatic BC patients treated with AI. TTP was significantly increased in patients with the rs4646 variant compared with the wild-type gene (hazard ratio (HR) = 0.51 [95 % confidence interval (CI), 0.33-0.78], P = 0.002). Seven studies analyzed the association between AEs with different polymorphisms of CYP19A1. Although there was a statistically significant association with musculoskeletal adverse events (rs934635, rs60271534, rs700518rs, and haplotype M_3_5) and with vasomotor symptoms (rs934635, rs1694189, rs7176005, and haplotype M_5_3) in individual studies, similar associations were not observed in further studies. No statistically significant association between musculoskeletal AEs and SNPs rs4646, rs10046, rs727479, and rs1062033 was found. CONCLUSIONS: These findings suggest that the presence of the rs4646 variant may be a predictive factor of the benefit of AI treatment for BC. The effects of CYP19A1 polymorphisms on clinical outcomes were most often detected in individual studies, suggesting that longer-term studies will better clarify these associations. Additional studies are needed to clarify the predictive value of other SNPs and whether CYP19A1 genotyping should be used to guide AI treatment.

Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder.

Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD.

ADHD pharmacogenetics across the life cycle: New findings and perspectives.

Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet completely understood, genetics plays a substantial role. Pharmacological treatment is considered effective and safe for children and adults, but there is considerable inter-individual variability among patients regarding response to medication, required doses, and adverse events. We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings, new approaches, limitations, and recommendations for future research. Our main findings are: first, the number of studies continues to grow, making ADHD one of the mental health areas with more pharmacogenetic studies. Second, there has been a focus shift on ADHD pharmacogenetic studies in the last years. There is an increasing number of studies assessing gene-gene and gene-environment interactions, using genome-wide association approaches, neuroimaging, and assessing pharmacokinetic properties. Third and most importantly, the heterogeneity in methodological strategies employed by different studies remains impressive. The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains unanswered. © 2014 Wiley Periodicals, Inc.

Insomnia Polygenic Component on Attention Deficit-Hyperactivity Disorder: Exploring this Association Using Genomic Data from Brazilian Families.

Introduction Insomnia is highly prevalent among individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the biological mechanisms shared between both conditions is still elusive. We aimed to investigate whether insomnia's genomic component is able to predict ADHD in childhood and adolescence. Methods A Brazilian sample of 259 ADHD probands and their biological parents were included in the study. Their genomic DNA genotypes were used to construct the polygenic risk score for insomnia (Insomnia PRS), using the largest GWAS summary statistics as a discovery sample. The association was tested using logistic regression, under a case-pseudocontrol design. Results Insomnia PRS was nominally associated with ADHD (OR = 1.228, p = 0.022), showing that the alleles that increase the risk for insomnia also increase the risk for ADHD. Discussion Our results suggest that genetic factors associated with insomnia may play a role in the ADHD genetic etiology, with both phenotypes likely to have a shared genetic mechanism.

Polymorphisms in the endothelial nitric oxide synthase gene in thalidomide embryopathy.

Thalidomide is one of the most potent teratogens known to humans. It is currently used for many clinical situations such as treatment of leprosy reactions and multiple myeloma. However, the teratogenic mechanisms by which it produces morphological defects still remain unclear. One of the hypotheses is the blockage of angiogenesis by reduction of nitric oxide (NO). In this study, we evaluated two functional polymorphisms of the endothelial nitric oxide synthase (eNOS) gene which is a constitutively expressed enzyme responsible for production of NO. The promoter -786T>C exon 7 (896G>T) polymorphisms were genotyped using real-time PCR for 28 individuals with thalidomide embryopathy (TE), 27 first-degree relatives of these individuals, and 68 individuals from the general population. Their allele, genotypic, and haplotypic frequencies were compared. A significant difference was observed in the -786T>C polymorphism genotypes (p=0.03) between the groups affected by TE and those unaffected (non-relatives). The TT genotype of the 896G>T polymorphism was observed in 10.7% of those affected and 2.9% of those unaffected, but the difference was not statistically significant (p=0.09). The haplotypic analysis indicated that the wild haplotype -786T/896G was distributed differently in the affected and unaffected groups (p=0.004). These results indicate that the individuals with TE have a higher frequency of alleles associated with lower expression of eNOS, indicating that this may be a genotype susceptible to TE.

Are polymorphisms in oestrogen receptors genes associated with lipid levels in response to hormone therapy?

BACKGROUND: Polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes are associated with intermediate or endpoint markers of cardiovascular disease and with the efficacy of postmenopausal hormone therapy (HT). Contradictory findings have been described in the past and the role of these genetics variants remains unclear. METHODS: A cross-sectional study was carried out with 266 postmenopausal women, of whom 115 received oral HT (HT+) and 151 did not receive any HT (HT-). We analysed three single-nucleotide polymorphisms (SNPs) in ESR1 (rs1801132, rs7757956 and rs2813544) and two in ESR2 (rs3020450 and rs7154455) and derived haplotypes with three additional polymorphisms that had been previously investigated by our group (ESR1 rs2234693 and ESR2 rs1256049 and rs4986938). RESULTS: The ESR1 rs2813544 polymorphism was associated with low-density lipoprotein cholesterol (LDL-C) in HT+ postmenopausal women (p = 0.044; pC = 0.388), while one ESR2 gene haplotype was associated with total cholesterol (T-chol) (p = 0.015; pC = 0.090) and LDL-C in HT+ postmenopausal women (p = 0.021; pC = 0.126). CONCLUSION: Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.

The Brazilian contribution to Attention-Deficit/Hyperactivity Disorder molecular genetics in children and adolescents.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric condition of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on a sufficient number of symptoms causing impairment in these two domains determining several problems in personal and academic life. Although genetic and environmental factors are important in ADHD etiology, how these factors influence the brain and consequently behavior is still under debate. It seems to be consensus that a frontosubcortical dysfunction is responsible, at least in part, for the ADHD phenotype spectrum. The main results from association and pharmacogenetic studies performed in Brazil are discussed. The investigations performed so far on ADHD genetics in Brazil and elsewhere are far from conclusive. New plausible biological hypotheses linked to neurotransmission and neurodevelopment, as well as new analytic approaches are needed to fully disclose the genetic component of the disorder.

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.

Caffeine-related genes influence anxiety disorders in children and adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (AD) frequently co-occur, increasing morbidity and challenging treatment. Caffeine is a central nervous system stimulant and acts in the brain through adenosine receptors, influencing attention, alertness, and anxiety. In the present study, we performed a gene-set analysis to verify if genes related to caffeine response are associated with anxiety disorders in 240 children and 406 adults with ADHD. We demonstrated an association between the gene-set with AD in children (P = 0.0054) and with the number of anxiety disorders in adults (P = 0.0197). In order to test if this effect is a result of anxiety in general or is related to AD comorbid with ADHD, we evaluated the association between caffeine gene-set with AD in an adult control sample. The gene-set was neither associated with the AD presence (P = 0.3008) nor with the number of AD (P = 0.5594) in this control sample. We also test this gene set with ADHD (n = 55,374) and AD (n = 18,186) GWAS summary statistics, and we did not observe significant results with ADHD (P = 0.5587) or AD (P = 0.3930). These findings suggest the caffeine-related genes play a role in the etiology of an anxiety disorder phenotype present in children and adults with ADHD.

Genetic influences on Alzheimer's disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil.

Alzheimer's disease is a complex neurodegenerative disorder. Several genes have been suggested as Alzheimer's susceptibility factors, the apolipoprotein E (APOE) gene being an established susceptibility gene and the genes coding angiotensin-converting enzyme (ACE) and apolipoprotein C1 (APOC1) being considered possible candidate genes for the disease. The objective of this study was to investigate the association of ACE and APOC1 gene polymorphisms with susceptibility to Alzheimer's disease and dementia in general, both alone and combined with the APOE gene. Forty-seven patients with dementia in general (35 of them with Alzheimer's disease) and 85 controls were investigated. The haplotypes E*3/-317*ins and E*4/-317*ins of APOE/APOC1 genes were significantly more frequent in the groups with Alzheimer's disease and dementia in general (P < 0.001). The frequency of the ACE*ins allele was also greater in the groups with Alzheimer's disease and dementia in general (P = 0.022; P = 0.045), but genotype frequencies were only different in groups without the E*4/-317*ins haplotype (P = 0.012 for Alzheimer's disease; P = 0.04 for dementia). Our data point to important genetic interactions involved in these diseases.

Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry.

AIMS: To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose-response and develop a model including genetic and non-genetic factors for warfarin dose prediction needed for each patient. METHODS: A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for -1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'-nuclease assays. RESULTS: The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, -1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed. CONCLUSION: The model suggested has one of the highest coefficients of determination among those described in the literature.

Evaluation of UGT1A1 and SULT1A1 polymorphisms with lipid levels in women with different hormonal status.

BACKGROUND: Estrogens influence many physiological processes including cardiovascular health. Polymorphisms in phase I and II estrogen metabolism enzymes are associated with lipid levels in women. METHODS: A cross-sectional study was carried out with 269 postmenopausal women, 116 who received oral hormonal therapy (HT) (39-75 years) with estrogens or estrogens plus progestagen, 153 that did not receive any HT (38-85 years), and 155 premenopausal women (18-52 years). Polymorphisms in UGT1A1 (rs5839491) and SULT1A1 (rs1042028) were analysed by PCR-based methods. Adjusted lipid levels means were compared among genotypes by one-way analysis of variance, with corrections for multiple testing. RESULTS: The UGT1A1*28 polymorphism was associated with total cholesterol (T-chol) (p = 0.030; corrected p = 0.060) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.011, corrected p = 0.022) in premenopausal women. The premenopausal and postmenopausal women, both carriers of SULT1A1*2/*2, had lower levels of T-chol and LDL-C means than carriers of the SULT1A1*1/*1 (p = 0.004, corrected p = 0.008 and 0.009, corrected p = 0.018, respectively). CONCLUSION: The data showed the presence of an association between the UGT1A1*28/*28 and SULT1A1*2/*2 and T-chol and LDL-C levels in women with different hormonal status. No previous studies investigated the association of the polymorphisms examined in this study with lipoprotein levels in women separately by hormonal status.

French Guiana Amerindian demographic history as revealed by autosomal and Y-chromosome STRs.

BACKGROUND: Previous investigations of French Guiana Amerindians performed by this group included blood group and protein genetic markers, mitochondrial DNA and Y-chromosome investigations. Molecular autosomal data and more extensive Y-chromosome determinations were lacking. SUBJECTS AND METHODS: The genetic variability of 15 autosome (ASTRs) and 17 Y-chromosome (YSTRs) microsatellite loci was studied in four French Guiana (Emerillon, Palikur, Wayampi, Kali'na) and one Brazilian (Apalai) Amerindian populations. A sixth group, the Peruvian Matsiguenga of the Maipurean linguistic family, was included in the data analysis since they could provide information about the past migration of people from that linguistic stock into northeastern Amazonia. RESULTS: Marked ASTR and YSTR variability was found, with 96% of the YSTR haplotypes being found in one population only. There was excellent agreement between the present and previous autosomal or uniparental results. Multidimensional scaling based on F(ST) genetic distances and population structure analysis revealed heterogeneity in gene distribution, with a clear difference between the Matsiguenga and Emerillon and the other groups. In the latter, Wilcoxon sign-rank test between observed and expected heterozygosity and the mode of allele frequency distribution revealed clues of a significant past genetic bottleneck. The Wayampi stand genetically closer to the Apalai, Palikur and Kali'na when examined for the autosome but not the Y-chromosome panel of markers, suggesting preferential female gene flow. CONCLUSION: The new data provided additional important information about the biological history of people from a remote South American region, indicating how gene diversity analyses can be used to increase understanding of human microevolutionary processes.

Sleep-related traits and attention-deficit/hyperactivity disorder comorbidity: Shared genetic risk factors, molecular mechanisms, and causal effects.

OBJECTIVES: To evaluate the shared genetic components, common pathways and causal relationship between ADHD and sleep-related phenotypes. METHODS: We used the largest genome-wide association summary statistics available for attention-deficit/hyperactivity disorder (ADHD) and various sleep-related phenotypes (insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype). We estimated the genomic correlation using cross-trait linkage disequilibrium score regression (LDSR) and investigated the potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect was estimated using two-sample Mendelian randomisation (TSMR), using the inverse variance weighted method as the main estimator. RESULTS: A positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD was observed. Insomnia, daytime sleepiness, and snoring shared genes with ADHD, that are involved in neurobiological functions and regulatory signalling pathways. The TSMR supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. CONCLUSION: Comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors that play an important role in neuronal signalling pathways. A causal effect of sleep disturbances and short sleep duration on ADHD reinforced their role as predictors of ADHD.

Host genetics influences the relationship between the gut microbiome and psychiatric disorders.

The gut microbiome is associated with psychiatric disorders; however, the molecular mechanisms mediating this association are poorly understood. The ability of host genetics to modulate the gut microbiome may be an important factor in understanding the association. In this study, we aimed to evaluate the role of genetic variants associated with the gut microbiome in the susceptibility of individuals to four psychiatric disorders: schizophrenia (SCZ), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and major depressive disorder (MDD). A total of 201 host genetic markers associated with microbiome outcomes and reported in available genome-wide association studies (GWAS) were included in the analyses. We searched for these variants in the summary statistics of the largest GWAS on these disorders to date, which were published by the Psychiatric Genomic Consortium, and performed gene-based and gene set association analyses. Two variants were significantly associated with ASD (rs9401458 and rs9401452) and one with MDD (rs75036654). For the gene-based association analysis, eight genes were associated with SCZ (ASIC2, KCND3, ITSN1, SIPA1L3, RBMS3, BANK1, CSMD1, and LHFPL3), one with MDD (ACTL8), two with ADHD (C14orf39 and FBXL17), and one with ASD (PINX). The gene set comprising 83 genes was associated with SCZ (p = 0.047). These findings suggest that genes related to microbiome composition may affect the susceptibility of individuals to psychiatric disorders, mainly schizophrenia. Although less robust, the associations with ASD, ADHD, and MDD cannot be discarded.