X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients.

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease. METHODS: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. RESULTS: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10-7 ). CONCLUSIONS: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.

BACKGROUND: Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause. METHODS: We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. RESULTS: Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function. CONCLUSION: Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.

Metabolic Profiling of the Soft Coral Erythropodium caribaeorum (Alcyonacea: Anthothelidae) from the Colombian Caribbean Reveals Different Chemotypes.

The Caribbean soft coral Erythropodium caribaeorum is a rich source of erythrolides-chlorinated briarane diterpenoids. These compounds have an ecological role as feeding deterrents, with a wide variation in their composition depending on the location where the sample is collected. In Colombia, this soft coral can be found at different locations in the Caribbean Sea including Santa Marta, Islas del Rosario, and Providencia-three environmentally different coral reef areas in the south and southwest Caribbean Sea. In order to evaluate differences in erythrolide composition, the metabolic profiles of samples from each of these locations were analyzed by HPLC-MS. Principal component analysis showed changes in the diterpene composition according to the sample origin. Diterpenes from samples collected at each location were isolated to describe the three chemotypes. The chemotype from Santa Marta was highly diverse, with the new erythrolides W and X together with eight known erythrolides. The sample from Islas del Rosario showed a low diversity chemotype constituted by high amounts of erythrolide A and B. The chemotype from Providencia showed low chemical diversity with only two main compounds-erythrolide V and R. Evaluation of cytotoxic activity against the human cancer cell lines PC-3, MCF7, and A549 showed erythrolides A and B as the more active compounds with IC50 values in the range from 2.45 to 30 µM.

The p.R47H Variant of TREM2 Gene is Associated With Late-onset Alzheimer Disease in Colombian Population.

OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in the triggering receptor expressed on myeloid cells 2 (TREM2) gene in a Colombian sample of late-onset Alzheimer disease (LOAD). METHODS: The p.Q33* (rs104894002), p.R47H (rs75932628), p.R62H (rs143332484), and p.D87N (rs142232675) variants of TREM2 gene were directly genotyped using KASPar technology in 358 cases and 329 healthy controls. Sanger sequencing was used to validate >10% of KASPar's results. The Fisher exact test was used to compare the distribution of allelic and genotype frequency between cases and controls, and the Bonferroni correction was set at P<0.05. RESULTS: The minor allele frequency of rs75932628-T was 0.009 in cases and was not found in any healthy controls which suggests a significant association between rs75932628-T and LOAD risk in our sample (P=0.010). The rs143332484-T variant did not exhibit a significant association (P=0.160), whereas rs104894002 and rs142232675 were not found. CONCLUSIONS: Our findings suggest that the rs75932628-T variant of TREM2 is an important risk factor for LOAD in the Colombian population.

Association Analysis of Polymorphisms in TOMM40, CR1, PVRL2, SORL1, PICALM, and 14q32.13 Regions in Colombian Alzheimer Disease Patients.

OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in different genes including APOE, TOMM40, CR1, PVRL2, SORL1, PICALM, and GWA_14q32.13 in a Colombian sample of Late-Onset Alzheimer disease (LOAD) patients. METHODS: A case-control study was conducted in 362 individuals (181 LOADs and 181 controls) to determine the association of single-nucleotide polymorphisms in APOE (e2, e3, and e4), TOMM40 (rs2075650), CR1 (rs665640), PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) with LOAD in a sample from Colombia. RESULTS: We were able to confirm the previously reported association of the APOE4 allele with AD. In addition, we report a new significant association with rs2075650 of TOMM40 for LOAD in our sample. We did not detect any significant interaction between TOMM40 and APOE4 carriers (heterozygous or homozygous) for disease risk development. However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele. In addition, the age of disease onset is earlier if APOE4/4 is present. CONCLUSION: Our findings suggest that rs2075650 of TOMM40 could be involved in earlier presentation of LOAD in the Colombian population.

Regulation of Oligodendrocyte Differentiation and Myelination by Nuclear Receptors: Role in Neurodegenerative Disorders.

During development and through adulthood, differentiation of diverse cell types is controlled by specific genetic and molecular programs for which transcription factors are master regulators of gene expression. Here, we present an overview of the role of nuclear receptors and their selective pharmacological modulators in oligodendrocytes linage, their role in myelination and remyelination and their potential use as a therapeutic strategy for demyelinating diseases. We discuss several aspects of nuclear receptors including: (1) the biochemistry of nuclear receptors superfamily; (2) their role on stem cells physiology, focusing in differentiation and cell removal; (3) the role of nuclear receptor in the oligodendrocytes cell linage, from oligodendrocyte progenitors cells to mature myelinating cells; and (4) the therapeutics opportunities of nuclear receptors for specific demyelinating diseases.

Scutellaria incarnata Vent. root extract and isolated phenylethanoid glycosides are neuroprotective against C2-ceramide toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuronal death is a central process in neurodegenerative diseases and represents a therapeutic challenge for their prevention and treatment. Scutellaria incarnata Vent. roots are used traditionally in Colombia for central nervous system conditions including those affecting cognitive functions, but their chemistry and neuroprotective action remain to be explored to understand the scientific basis for their medicinal uses. In this study, S. incarnata roots are investigated to assess whether they have neuroprotective effects that could provide some explanation for their traditional use in neurodegenerative diseases. AIM OF THE STUDY: To evaluate the neuroprotective effect of S. incarnata roots and its chemical constituents against C2-ceramide-induced cell death in Cath.-a-differentiated (CAD) cells. MATERIALS AND METHODS: S. incarnata root ethanol extract was fractionated and compounds were isolated by column chromatography; their structures were elucidated by nuclear magnetic resonance spectroscopy, mass spectrometry and infrared spectroscopy. The cytotoxic and neuroprotective effects against C2-ceramide of S. incarnata root extract, fractions and isolated compounds were assessed in CAD cells. RESULTS: S. incarnata root extract and its n-butanol fraction were not cytotoxic but showed neuroprotective effects against C2-ceramide toxicity in CAD cells. The phenylethanoid glycosides incarnatoside (isolated for the first time) and stachysoside C (12.5, 25 and 50 µg/mL) from S. incarnata roots also protected CAD cells against C2-ceramide without inducing cytotoxic effects. CONCLUSION: The observed neuroprotective effects of S. incarnata root extract and isolated phenylethanoid glycosides in CAD cells provide an ethnopharmacological basis for the traditional use of this species in Colombia for central nervous system disorders.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson Disease.

Sex differences in Parkinson Disease (PD) risk are well-known. However, it is still unclear the role of sex chromosomes in the development and progression of PD. We performed the first X-chromosome Wide Association Study (XWAS) for PD risk in Latin American individuals. We used data from three admixed cohorts: (i) Latin American Research consortium on the GEnetics of Parkinson's Disease (n=1,504) as discover cohort and (ii) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (iii) Bambui Aging cohort (n= 1,442) as replication cohorts. After developing a X-chromosome framework specifically designed for admixed populations, we identified eight linkage disequilibrium regions associated with PD. We fully replicated one of these regions (top variant rs525496; discovery OR [95%CI]: 0.60 [0.478 - 0.77], p = 3.13 × 10 -5 ; replication OR: 0.60 [0.37-0.98], p = 0.04). rs525496 is an expression quantitative trait loci for several genes expressed in brain tissues, including RAB9B, H2BFM, TSMB15B and GLRA4 . We also replicated a previous XWAS finding (rs28602900), showing that this variant is associated with PD in non-European populations. Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

BACKGROUND: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. METHODS: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort. RESULTS: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall. CONCLUSION: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts.

Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease.

Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.

Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): report of three affected sibs.

The Wiedemann-Rautenstrauch syndrome (WRS) (OMIM 264090) is a rare progeroid entity. WRS patients are characterized by premature aging present at birth including pseudohydrocephalus, cranio-facial disproportion, reduced subcutaneous fat, thin skin, rigid and thick joints, and neonatal teeth in some cases. Here we describe three sibs with WRS from unaffected parents and without consanguinity. Our findings support autosomal recessive inheritance in WRS and support the possibility of homozygocity mapping as a good approach to find the causative gene.

Differential Regulation of the EGFR/PI3K/AKT/PTEN Pathway between Low- and High-Grade Gliomas.

Gliomas represent 70% of all central system nervous tumors and are classified according to the degree of malignancy as low- or high-grade. The permanent activation of the EGFR/PI3K/AKT pathway by various genetic or post-translational alterations of EGFR, PI3KCA, and PTEN has been associated with increased proliferation and resistance to apoptosis. The present study aimed to analyze the molecular/genetic changes in the EGFR/PI3K/AKT/PTEN pathway between low-grade and high-grade gliomas in a sample of Colombian patients. A total of 30 samples were tested for PI3K and PTEN mutations, EGFR, PI3K, and AKT gene amplification, AKT, PI3K, BAX, Bcl2 expression levels, and phosphorylation of AKT and PTEN, EGFR and/or PI3K gene amplification was found in 50% of low-grade and 45% of high-grade ones. AKT amplification was found in 25% of the low-grade and 13.6% of the high-grade. The expression of PI3K, AKT, Bcl2, and BAX was increased particularly to a high degree. AKT phosphorylation was found in 66% of low-grade and 31.8% of high-grade. Increased phosphorylation of PTEN was found in 77% low-grade and 66% high-grade. Our results indicate that alterations in the EGFR/PI3K/AKT/PTEN pathway could be important in the initiation and malignant progression of this type of tumor.

Retinoid X receptor activation promotes re-myelination in a very old triple transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aß peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.

Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration.

The present review explores the role of ceramides in neuronal apoptosis, as well as the recent discovery of the signaling pathways involved in this process placing particular emphasis on the correlation between cellular metabolism and neuronal death. Endogenous levels of ceramides are increased following various pro-apoptotic stimuli which have been identified as potential causes of chronic and acute neurodegenerative diseases. Ceramides induce changes in multiple enzymes and cell signaling components. The early inhibition of the neuronal survival pathway regulated by phosphatidil-inositol-3-kinase/protein kinase B or AKT mediated by ceramide may be a relevant early event in the decision of neuronal survival/death. It may perturb several molecular and metabolic functions. In particular it might decrease glycolysis through rapid modulation of hexokinase activity. This would in turn generate limited amounts of mitochondrial substrates leading to mitochondrial dysfunction and neuronal apoptosis. Subtle and early metabolic alterations caused by inhibition of the PI3K/AKT pathway mediated by ceramide may potentially work with genes associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Together they may be determinant steps in downstream events leading to neuronal apoptosis. Therefore, reinforcement of the PI3K/AKT pathway could constitute an important neuroprotective strategy.

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts.

Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.

Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients.

The Wiedemann-Rautenstrauch syndrome (WRS, OMIM: 264090) characterizes a premature aging syndrome in which several features of aging are apparent at birth. We did not find mutations in Lamin A/C (LMNA) gene in four WRS patients, and in particular, we did not find the G608G mutation (GGC > GGT transition) which is associated with most cases with Hutchinson-Gilford progeria (OMIM 176670). These findings suggest that WRS represents a distinct progeroid entity that may be caused by recessive mutations of a different gene.

Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity. METHODS: We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses. RESULTS: A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences. LIMITATIONS: Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles. CONCLUSION: To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.