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.

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.

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.

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.

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.

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.

Obesity and ADHD: Exploring the role of body composition, BMI polygenic risk score, and reward system genes.

The association between obesity and attention-deficit hyperactivity disorder (ADHD) has been extensively reported in the literature. However, the potential mechanisms underlying this association are not completely understood. This study aimed to evaluate the association between body composition and ADHD and explore the possible genetic mechanisms involved. We used data from the 1982 Pelotas (Brazil) Birth Cohort at age 30-year follow-up (N = 3630). We first used logistic regression analysis to test whether body mass index (BMI), fat mass (FM), and fat-free mass (FFM) were associated with ADHD. We further tested the association between BMI polygenic risk score (BMI-PRS) and ADHD and the role of the genes upregulated in the reward system using a gene-set association approach. BMI (odds ratio [OR] = 1.05; 95% confidence interval [CI], 1.00-1.09; p = 0.038) and FM (OR = 1.04; 95% CI, 1.00-1.07; p = 0.043) were associated with ADHD. The BMI-PRS was associated with ADHD (using p-value threshold (PT) = 0.4; OR = 1.65; 95% CI, 1.02-2.65) at a nominal level. In gene-set analysis, the reward system genes were associated with BMI in subjects with a high BMI-PRS score, considering PT = 0.4 (p = 0.014). The results suggest that BMI genetic components, especially those genes related to the reward system, may be involved in this association.

NR3C1, ABCB1, TNF and CYP2C19 polymorphisms association with the response to the treatment of erythema nodosum leprosum.

Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.

Synergistic effects between ADORA2A and DRD2 genes on anxiety disorders in children with ADHD.

The prevalence of anxiety disorders in patients with Attention Deficit/Hyperactivity Disorder (ADHD) is around 15-40%, three times higher than in the general population. The dopaminergic system, classically associated with ADHD, interacts directly with the adenosinergic system through adenosine A2A receptors (A2A) and dopamine D2 receptors (D2) forming A2A-D2 heterodimers. Both dopaminergic and adenosinergic systems are implicated in anxiety disorders. Therefore, the aims of this study were: a) to investigate the main effects of ADORA2A and DRD2 gene variants on anxiety disorders in an ADHD sample of children and adolescents; b) to test potential synergism between ADORA2A and DRD2 genes on the same outcome; c) to explore ADORA2A variants functionality using an in silico approach. The sample consists of 478 children and adolescents with ADHD and their parents, totalizing 1.239 individuals. An association between the ADORA2A rs2298383 TT genotype with the presence of anxiety disorders (P = .004) and an interaction between ADORA2A-DRD2 risk haplotypes with the same outcome (P = .005) was detected. The in silico analyses showed that rs2298383 has the highest score for regulatory function among all variants in the ADORA2A gene described up to date. Altogether, the present findings suggested that the ADORA2A gene and the interaction of ADORA2A and DRD2 genes may play a role in anxiety disorders in children and adolescents with ADHD.

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.

Angiogenesis-related genes and thalidomide teratogenesis in humans: an approach on genetic variation and review of past in vitro studies.

Thalidomide embryopathy (TE) has affected more than 10,000 babies worldwide. The hypothesis of antiangiogenesis as the teratogenic mechanism of thalidomide has been investigated in several experimental models; but, in humans, it has only been accessed by in vitro studies. Here, we hypothesized the effect of thalidomide upon angiogenesis-related molecules or proteins, previously identified in human embryonic cells, through the in silico STRING-tool. We also investigated ten polymorphisms in angiogenesis-related genes in 38 Brazilian TE individuals and 136 non-affected Brazilians. NOS2, PTGS2, and VEGFA polymorphisms were chosen for genotyping. The STRING-tool suggested nitric oxide and ß-catenin as the central angiogenesis-related molecules affected by thalidomide's antiangiogenic property. We did not identify a significant difference of allelic, genotypic or haplotypic frequencies between the groups. We could not predict a risk allele or a protective one for TE in NOS2, PTGS2, or VEGFA, although other genes should be analyzed in larger samples. The role of nitric oxide and ß-catenin must be further evaluated, regarding thalidomide teratogenesis complex etiology.

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.

Genomic and in silico analyses of CRBN gene and thalidomide embryopathy in humans.

Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a thalidomide target protein encoded by CRBN gene, have helped to understand thalidomide therapeutic and teratogenic properties. We sequenced CRBN-thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group (p=0.04). The genotype rs1620675 CC was related to neurological anomalies in TE individuals (p=0.004). Bioinformatics analysis suggested this genotype leads to potential alterations in splicing sites and binding to transcription factors. Comparison of the Cereblon-thalidomide binding domains in mammals demonstrated that CRBN is highly conserved across species. All the variants require evaluation in functional assays in order to understand their role in Cereblon-thalidomide binding and complex interactions that lead to TE.

COMT and prenatal maternal smoking in associations with conduct problems and crime: the Pelotas 1993 birth cohort study.

Conduct problems in childhood and adolescence are significant precursors of crime and violence in young adulthood. The purpose of the current study is to test the interaction between prenatal maternal smoking and COMT Val(158)Met in conduct problems and crime in the 1993 Pelotas Birth Cohort Study. Conduct problems were assessed through the parent version of the Strengths and Difficulties Questionnaire at ages 11 and 15 years. A translated version of a confidential self-report questionnaire was used to collect criminal data at 18 years of age. Negative binomial regression analyses showed an association between prenatal maternal smoking and SDQ conduct problem scores (IRR = 1.24; 95% CI: 1.14-1.34; p < 0.001) at 11 years of age. However, no evidence was found for an association between COMT genotypes and conduct scores or for an interaction between maternal smoking and this gene in predicting conduct problems. Very similar results were obtained using the 15 years conduct scores and crime measure at age 18. Prenatal maternal smoking was associated with crime (IRR = 1.28; 95% CI: 1.09-1.48; p = 0.002) but neither COMT genotypes nor the possible interaction between gene and maternal smoking were significantly associated with crime. Replications of GxE findings across different social contexts are critical for testing the robustness of findings.

New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (-786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles -786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2-5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue.

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.

Genetics of attention-deficit/hyperactivity disorder: an update.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting children, adolescents, and adults. The prevalence is estimated at 5 to 7% of school-aged children and 2.5 to 5% of adults. The phenotype is complex and heterogeneous, presenting variable clinical features, developmental course, and outcome. The genetic susceptibility to ADHD is attributed to both common and rare variants from a broad range of genes related mainly to neurotransmission and neurodevelopment pathways. However, it has been difficult to identify the genetic risk variants that account for the high heritability of this disorder. In this paper, we present recent findings from molecular genetics studies on both child and adult ADHD. Challenges and future directions for ADHD genetic studies are reviewed and discussed.

PON1 polymorphisms are predictors of ability to attain HDL-C goals in statin-treated patients.

OBJECTIVES: PON1 plays an important role in inhibiting LDL-C oxidation, which reduces atherosclerosis and cardiovascular disease. Elevated PON1 activity or levels may contribute to increased HDL-C levels, but controversy exists over the hypothesis that genetic variation in the PON1 gene locus modulates HDL-C levels and responses to statin treatment. Therefore, the objective of this study was to investigate the association between two polymorphisms in the PON1 gene and statin responses in a south Brazilian population. DESIGN AND METHODS: The study population included 433 dyslipidemic patients who were prescribed statins. Total cholesterol, triglyceride, HDL-C and LDL-C levels were measured in these patients both before and after approximately 6months of treatment with simvastatin/atorvastatin. Genotypes were assessed by real-time PCR for two PON1 polymorphisms, Q192R (rs662) and L55M (rs854560). RESULTS: Baseline lipid levels were not associated with Q192R or L55M polymorphisms. For the Q192R (rs662) polymorphism, we observed that HDL-C goals were attained less often in patients with RR homozygosity than in Q allele carriers (χ(2) P=0.009, adjusted residual analysis P=0.003). For the L55M (rs854560) polymorphism, LL homozygotes were underrepresented among subjects that achieved the HDL-C goal (χ(2) P=0.026, adjusted residual analysis P=0.008). Analysis by univariate logistic regression confirmed that QQ/QR and MM/ML carriers had an increased chance of attaining HDL-C goals (OR=2.41, CI95%=1.32-4.40, P=0.004 and OR=1.68, CI95%=1.15-2.45, P=0.008). In a multivariate logistic analysis used to assess predictors of attaining an HDL-C goal>1.55mmol/L, we observed that gender (OR=1.71, CI95%=1.04-2.83, P=0.036), baseline HDL-C levels (OR=1.13, CI95%=1.10-1.16, P<0.001) and the QQ/QR+MM/ML genotypes increased the chance of achieving HDL-C goals (OR=2.81, CI95%=1.35-5.85, P=0.006). CONCLUSIONS: The results of this study show that the Q192R (rs662) and L55M (rs854560) polymorphisms may play a role in interindividual variation in achievement of HDL-C goals in response to statins.

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.