Mapping of long interspersed element-1 (L1) insertions by TIPseq provides information about sub chromosomal genetic variation in human embryos.

PURPOSE: Retrotransposons play important roles during early development when they are transiently de-repressed during epigenetic reprogramming. Long interspersed element-1 (L1), the only autonomous retrotransposon in humans, comprises 17% of the human genome. We applied the Single Cell Transposon Insertion Profiling by Sequencing (scTIPseq) to characterize and map L1 insertions in human embryos. METHODS: Sixteen cryopreserved, genetically tested, human blastocysts, were accessed from consenting couples undergoing IVF at NYU Langone Fertility Center. Additionally, four trios (father, mother, and embryos) were also evaluated. scTIPseq was applied to map L1 insertions in all samples, using L1 locations reported in the 1000 Genomes as controls. RESULTS: Twenty-nine unknown and unique insertions were observed in the sixteen embryos. Most were intergenic; no insertions were located in exons or immediately upstream of genes. The location or number of unknown insertions did not differ between euploid and aneuploid embryos, suggesting they are not merely markers of aneuploidy. Rather, scTIPseq provides novel information about sub-chromosomal structural variation in human embryos. Trio analyses showed a parental origin of all L1 insertions in embryos. CONCLUSION: Several studies have measured L1 expression at different stages of development in mice, but this study for the first time reports unknown insertions in human embryos that were inherited from one parent, confirming no de novo L1 insertions occurred in parental germline or during embryogenesis. Since one-third of euploid embryo transfers fail, future studies would be useful for understanding whether these sub-chromosomal genetic variants or de novo L1 insertions affect embryo developmental potential.

A pilot study of LINE-1 copy number and telomere length with aging in human sperm.

PURPOSE: Unlike other cells in the body, in sperm, telomere length (TL) increases with age. TL can regulate nearby genes, and the subtelomeric region is rich in retrotransposons. We hypothesized that age-related telomere lengthening in sperm might suppress Long Interspersed Element 1 (LINE-1/L1), the only competent retrotransposon in humans. METHODS: We measured L1 copy number (L1-CN) and sperm telomere length (STL) from young and older men to evaluate the relationship between age, TL and L1-CN. We also evaluated L1-CN and TL in individual sperm to determine whether these variables influence sperm morphology. STL was assayed by Multiplex quantitative polymerase chain reaction method (mmqPCR) and L1-CN by Quantitative polymerase chain reaction (qPCR). RESULTS: We found that STL increased, and L1-CN decreased significantly with paternal age. STL in normal single sperm was significantly higher than in abnormal sperm. L1-CN did not differ between normal and abnormal sperm. Furthermore, morphologically normal sperm have longer telomeres than abnormal sperm. CONCLUSIONS: Elongation of telomeres in the male germline could repress retrotransposition, which tends to increase with cellular aging. More studies in larger cohorts across a wide age span are needed to confirm our conclusions and explore their biological and clinical significance.

Transposon insertion profiling by sequencing (TIPseq) identifies novel LINE-1 insertions in human sperm.

PURPOSE: Long interspersed nuclear element-1 (LINE-1 or L1) comprises 17% of the human genome. Retrotransposons may perturb gene integrity or alter gene expression by altering regulatory regions in the genome. The germline employs a number of mechanisms, including cytosine methylation, to repress retrotransposon transcription throughout most of life. Demethylation during germ cell and early embryo development de-represses retrotransposons. Intriguingly, de novo genetic variation appearing in sperm has been implicated in a number of disorders in offspring, including autism spectrum disorder, schizophrenia, and bipolar disorder. We hypothesize that human sperm exhibit de novo retrotransposition and employ a new sequencing method, single cell transposon insertion profiling by sequencing (scTIPseq) to map them in small amounts of human sperm. METHODS: Cross-sectional case-control study of sperm samples (n=10 men; ages 32-55 years old) from consenting men undergoing IVF at NYU Langone Fertility Center. scTIPseq identified novel LINE-1 insertions in individual sperm and TIPseqHunter, a custom bioinformatics pipeline, compared the architecture of sperm LINE-1 to known LINE-1 insertions from the European database of Human specific LINE-1 (L1Hs) retrotransposon insertions (euL1db). RESULTS: scTIPseq identified 17 novel insertions in sperm. New insertions were mainly intergenic or intronic. Only one sample did not exhibit new insertions. The location or number of novel insertions did not differ by paternal age. CONCLUSION: This study for the first time reports novel LINE-1 insertions in human sperm, demonstrating the feasibility of scTIPseq, and identifies new contributors to genetic diversity in the human germ line.

Genetic polymorphisms and their effects on the severity of silicosis in workers exposed to silica in Brazil.

OBJECTIVE: Silicosis is a pneumoconiosis characterized by fibrosis of the lung parenchyma caused by inhalation of silica particles. Genetic factors might play a role in the severity silicosis. We sought to evaluate the influence of polymorphisms in the ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1, and TNF genes on the severity of silicosis. METHODS: Nine polymorphisms were genotyped by PCR in a sample of 143 patients with silicosis in the state of Rio de Janeiro, Brazil. RESULTS: Fifty-seven patients (40%) were classified as having simple silicosis and 86 (60%) were classified as having complicated silicosis. The TT genotype of rs1800469 in the TGFB1 gene showed a protective effect for complicated silicosis (OR = 0.35; 95% CI, 0.14-0.92; p = 0.028) when compared with the other two genotypes (CC+CT). The polymorphic T allele of rs763110 in the FASLG gene (OR = 0.56; 95% CI, 0.31-0.99; p = 0.047), as well as a dominant model for the T allele (TT+CT: OR = 0.37; 95% CI, 0.15-0.96; p = 0.037), also showed a protective effect. When patients with simple silicosis despite having been exposed to silica for a longer time (> 44,229 hours) were compared with patients with complicated silicosis despite having been exposed to silica for a shorter time, the T allele of rs763110 in the FASLG gene (OR = 0.20; 95% CI, 0.08-0.48; p < 0.0001), as well as dominant and recessive models (OR = 0.06; 95% CI, 0.00-0.49; p = 0.01 and OR = 0.22; 95% CI, 0.06-0.77; p = 0.014, respectively), showed a protective effect against the severity of silicosis. CONCLUSIONS: It appears that rs1800469 polymorphisms in the TGFB1 gene and rs763110 polymorphisms in the FASLG gene are involved in the severity of silicosis. Given the lack of studies relating genetic polymorphisms to the severity of silicosis, these results should be replicated in other populations.

Telomere fusions as a signal of term placental aging? A pilot study.

Lay summary: The placenta plays an essential role at the beginning of life, nourishing and supporting the fetus, but its life span is limited. In late pregnancy, the placenta develops signs of aging, including inflammation and impaired function, which may complicate pregnancy. Placentas also show another sign of aging - cells with extra or missing chromosomes. Chromosomally abnormal cells could gather in the placenta if they get stranded there and/or if the cells do not separate normally. Chromosome separation goes wrong in aging cells when the DNA sequences, which protect the ends of the chromosomes, erode. When chromosomes lose their protective caps, they fuse which leads to abnormal numbers of chromosomes. In this pilot study, for the first time, we found fusions between the caps in a human placenta when it reaches full term. More studies are needed to decide whether this has an influence on how the placenta works and outcomes of pregnancy.

Impact of superovulation and in vitro fertilization on LINE-1 copy number and telomere length in C57BL/6 J mice blastocysts.

OBJECTIVE: Millions of babies have been conceived by IVF, yet debate about its safety to offspring continues. We hypothesized that superovulation and in vitro fertilization (IVF) promote genomic changes, including altered telomere length (TL) and activation of the retrotransposon LINE-1 (L1), and tested this hypothesis in a mouse model. MATERIAL AND METHODS: Experimental study analyzing TL and L1 copy number in C57BL/6 J mouse blastocysts in vivo produced from natural mating cycles (N), in vivo produced following superovulation (S), or in vitro produced following superovulation (IVF). We also examined the effects of prolonged culture on TL and L1 copy number in the IVF group comparing blastocysts cultured 96 h versus blastocysts cultured 120 h. TL and L1 copy number were measured by Real Time PCR. RESULTS: TL in S (n = 77; Mean: 1.50 ± 1.15; p = 0.0007) and IVF (n = 82; Mean: 1.72 ± 1.44; p < 0.0001) exceeded that in N (n = 16; Mean: 0.61 ± 0.27). TL of blastocysts cultured 120 h (n = 15, Mean: 2.14 ± 1.05) was significantly longer than that of embryos cultured for 96 h (n = 67, Mean: 1.63 ± 1.50; p = 0.0414). L1 copy number of blastocysts cultured for 120 h (n = 15, Mean: 1.71 ± 1.49) exceeded that of embryos cultured for 96 h (n = 67, Mean: 0.95 ± 1.03; p = 0.0162). CONCLUSIONS: Intriguingly ovarian stimulation, alone or followed by IVF, produced embryos with significantly longer telomeres compared to in vivo, natural cycle-produced embryos. The significance of this enriched telomere endowment for the health and longevity of offspring born from IVF merit future studies.

Control of LINE-1 Expression Maintains Genome Integrity in Germline and Early Embryo Development.

Maintenance of genome integrity in the germline and in preimplantation embryos is crucial for mammalian development. Epigenetic remodeling during primordial germ cell (PGC) and preimplantation embryo development may contribute to genomic instability in these cells, since DNA methylation is an important mechanism to silence retrotransposons. Long interspersed elements 1 (LINE-1 or L1) are the most common autonomous retrotransposons in mammals, corresponding to approximately 17% of the human genome. Retrotransposition events are more frequent in germ cells and in early stages of embryo development compared with somatic cells. It has been shown that L1 activation and expression occurs in germline and is essential for preimplantation development. In this review, we focus on the role of L1 retrotransposon in mouse and human germline and early embryo development and discuss the possible relationship between L1 expression and genomic instability during these stages. Although several studies have addressed L1 expression at different stages of development, the developmental consequences of this expression remain poorly understood. Future research is still needed to highlight the relationship between L1 retrotransposition events and genomic instability during germline and early embryo development.

Genetic polymorphisms and their effects on the severity of silicosis in workers exposed to silica in Brazil / Polimorfismos genéticos e seus efeitos na gravidade da silicose em trabalhadores expostos à sílica no Brasil

ABSTRACT Objective: Silicosis is a pneumoconiosis characterized by fibrosis of the lung parenchyma caused by inhalation of silica particles. Genetic factors might play a role in the severity silicosis. We sought to evaluate the influence of polymorphisms in the ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1, and TNF genes on the severity of silicosis. Methods: Nine polymorphisms were genotyped by PCR in a sample of 143 patients with silicosis in the state of Rio de Janeiro, Brazil. Results: Fifty-seven patients (40%) were classified as having simple silicosis and 86 (60%) were classified as having complicated silicosis. The TT genotype of rs1800469 in the TGFB1 gene showed a protective effect for complicated silicosis (OR = 0.35; 95% CI, 0.14-0.92; p = 0.028) when compared with the other two genotypes (CC+CT). The polymorphic T allele of rs763110 in the FASLG gene (OR = 0.56; 95% CI, 0.31-0.99; p = 0.047), as well as a dominant model for the T allele (TT+CT: OR = 0.37; 95% CI, 0.15-0.96; p = 0.037), also showed a protective effect. When patients with simple silicosis despite having been exposed to silica for a longer time (> 44,229 hours) were compared with patients with complicated silicosis despite having been exposed to silica for a shorter time, the T allele of rs763110 in the FASLG gene (OR = 0.20; 95% CI, 0.08-0.48; p < 0.0001), as well as dominant and recessive models (OR = 0.06; 95% CI, 0.00-0.49; p = 0.01 and OR = 0.22; 95% CI, 0.06-0.77; p = 0.014, respectively), showed a protective effect against the severity of silicosis. Conclusions: It appears that rs1800469 polymorphisms in the TGFB1 gene and rs763110 polymorphisms in the FASLG gene are involved in the severity of silicosis. Given the lack of studies relating genetic polymorphisms to the severity of silicosis, these results should be replicated in other populations.

RESUMO Objetivo: A silicose é uma pneumoconiose caracterizada por fibrose do parênquima pulmonar causada por inalação de partículas de sílica. Fatores genéticos podem desempenhar um papel na gravidade da silicose. Nosso objetivo foi avaliar a influência de polimorfismos dos genes ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1 e TNF na gravidade da silicose. Métodos: Nove polimorfismos foram genotipados por meio de PCR em uma amostra composta por 143 pacientes com silicose no estado do Rio de Janeiro, Brasil. Resultados: A silicose foi classificada em simples em 57 (40%) dos pacientes e em complicada, em 86 (60%). O genótipo TT do polimorfismo rs1800469 do gene TGFB1 teve efeito protetor contra a silicose complicada (OR = 0,35; IC95%: 0,14-0,92; p = 0,028) em comparação com os outros dois genótipos (CC+CT). O alelo T polimórfico do polimorfismo rs763110 do gene FASLG (OR = 0,56; IC95%: 0,31-0,99; p = 0,047) e um modelo dominante do alelo T (TT+CT: OR = 0,37; IC95%: 0,15-0,96; p = 0,037) também tiveram efeito protetor. Quando se compararam os pacientes que tinham silicose simples com um tempo maior de exposição à sílica (> 44.229 horas) àqueles que tinham silicose complicada com um tempo menor de exposição à sílica, o alelo T do polimorfismo rs763110 do gene FASLG (OR = 0,20; IC95%: 0,08-0,48; p < 0,0001) e modelos dominantes e recessivos (OR = 0,06; IC95%: 0,00-0,49; p = 0,01 e OR = 0,22; IC95%: 0,06-0,77; p = 0,014, respectivamente) tiveram efeito protetor contra a gravidade da silicose. Conclusões: Polimorfismos rs1800469 do gene TGFB1 e polimorfismos rs763110 do gene FASLG parecem estar envolvidos na gravidade da silicose. Como há poucos estudos que tenham estabelecido relações entre polimorfismos genéticos e a gravidade da silicose, esses resultados devem ser replicados em outras populações.

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development.

IMPORTANCE: It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction. OBJECTIVE: In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos. EVIDENCE ACQUISITION: We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development. RESULTS: Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos. CONCLUSIONS AND RELEVANCE: Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.

Identification of a Rare and Potential Pathogenic MC4R Variant in a Brazilian Patient With Adulthood-Onset Severe Obesity.

BACKGROUND: The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity. METHODS: This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0-11 years), 19 patients in the adolescence/youth-onset group (12-21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject's DNA was assessed using automated Sanger sequencing. RESULTS: Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity. CONCLUSION: This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

Is individual genetic susceptibility a link between silica exposure and development or severity of silicosis? A systematic review.

BACKGROUND: Silicosis is a lung disease of fibrotic nature resulting from the inhalation and deposition of dust containing crystalline silica. Subjects exposed to the same environmental factors may show distinct radiological manifestations, and since silicosis is known as a multifactorial disease, it is plausible that individual genetic susceptibility may play a role in the pathology. This review of the literature aims to provide an assessment of the present data on the genetic association studies in silicosis and describe the genes that potentially might influence silicosis susceptibility in silica-exposed individuals. METHODS: We accessed the database of PubMed for articles published in English about interindividual genetic susceptibility to silicosis using terms related to the subject matter. RESULTS: Following the evaluation process, 28 studies were included in this systematic review, including 23 original studies and 5 meta-analyses. CONCLUSIONS: Regardless of the advances in the knowledge of the importance of gene variations in silicosis, more studies need to be performed, in particular, special polygenic and genome-wide investigations.

Telomere erosion as a placental clock: From placental pathologies to adverse pregnancy outcomes.

The placenta provides nutritional and gas exchange between fetus and mother. Early in pregnancy, placental trophoblasts proliferate rapidly and invade aggressively. As pregnancy progresses, placental cells begin to age. Indeed, pregnancy itself has a tightly regulated duration, determined in large part by placental lifespan. Late in pregnancy, placental cells reach a senescent apoptotic state, activated by a number of intrinsic and extrinsic factors, including oxidative stress (OS), and DNA damage. Pregnancy complications, stillbirths and neonatal deaths have been related to OS and abnormal placental aging. Telomeres, the protective nucleoprotein structures at the ends of linear chromosomes, shorten both from cell replication and from exposure to OS. When telomeres become critically short they trigger cell cycle arrest and eventually cell death. Telomere attrition thus provide an intrinsic mechanism to explain tissue senescence and aging. Mounting evidence suggests that senescence of placental and fetal membrane cells results from telomere attrition. We review the studies that have addressed the role of telomere length (TL) in placentas from normal and complicated pregnancies, including pre-eclampsia, intrauterine growth restriction, gestational diabetes, and stillbirth. To date studies have uncovered associations between TL and a number of obstetrical complications. Future research is needed to determine whether these associations are causative, i.e. whether these clinical conditions result from telomere dysfunction, and whether particular features of telomeres, e.g. mean or shortest length, etc. could serve as clinically useful biomarkers of placental health.

Interleukin 1α and 1ß gene variations are associated with tuberculosis in silica exposed subjects.

INTRODUCTION: Silicosis is a fibrotic lung disease resulting from the inhalation of crystalline silica and can be classified as simple or complicated according to the International Labour Organization criteria. Furthermore, individuals exposed to crystalline silica also have a higher risk for the development of tuberculosis (Tb). The contribution of inflammatory cytokines to the risk of silicosis and Tb in different populations has previously been reported. Since genetic background might be related to susceptibility to silicosis and Tb, the study of polymorphisms within IL-1α, IL-1ß, and tumor necrosis factor protein-coding genes may contribute to elucidating the genetic basis of these diseases. METHODS: Single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction using restriction fragment length polymorphism or by Taqman methodology, in a sample of 102 silica-exposed patients from Brazil. RESULTS: No significant associations were observed between the SNPs studied and the severity of silicosis. However, significant associations were found between Tb and the C allele (odds ratio [OR] = 1.93, 95% confidence interval [CI], 1.01-3.73) and the CC genotype (OR = 2.34, 95% CI, 1.04-5.31) of IL1A -899C>T. The IL1B +3954C>T polymorphism also showed an association with Tb (T allele dominant model OR = 2.38, 95% CI, 1.04-5.41). CONCLUSION: These preliminary results demonstrate that the IL1A and IL1B gene variations may contribute to some extent to susceptibility to Tb, but not silicosis. However, additional studies are still needed to confirm these results.

OLIG2 gene polymorphisms are associated with nasty, unpleasant and uncontrollable thoughts in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is one of 10 major debilitating neuropsychiatric disorders, according to the World Health Organization (WHO), affecting around 2.3% of people worldwide. Obsessive-compulsive symptoms are caused by shared or distinct genetic or environmental influences. Several imaging studies have detected white-matter alterations in OCD, and recent studies have demonstrated thatOCD is associated with variations in the OLIG2 gene. The aim of this study was to investigate whether OLIG2 gene is associated with OCD and its clinical features in a Brazilian sample. We genotyped three variants in OLIG2 gene, rs762178, rs1059004, and rs9653711 in 205 OCD patients and 202 healthy controls by Taqman® methodology. Genotypes and alleles distributions were analyzed by χ2 or Fisher exact tests. The rs762178 and rs9653711 polymorphisms were significantly associated with OCD (P = 0.048 and 0.029, respectively). We also observed an association of rs1059004 and rs9653711 with the presence of Obsessive-Compulsive Inventory-Revised (OCI-R) obsessing (unacceptable thoughts) subscore (P = 0.031 and 0.034, respectively). Moreover, the pair of loci consisting of rs762178 and rs9653711 A-G haplotype was associated with OCD (P < 0.0001). The OLIG2 gene may be involved in OCD, particularly in patients showing nasty, unpleasant and uncontrollable thoughts. However, more studies in larger samples are needed to replicate these findings.

Association analyses reveal gender-specific associations of DAT1 40-bp VNTR and -839C/T polymorphisms with obsessive-compulsive disorder and obsessive-compulsive symptoms.

The dopamine transporter (DAT) is involved in dopamine signaling and distribution, controlling dopamine concentrations and contributing to several central nervous system disorders. The purpose of this study was to determine the association between two functional polymorphisms in DAT1 gene, the 40-base pair Variable Number of Tandem Repeats (VNTR) and the Single Nucleotide Polymorphism (SNP) -839C/T and obsessive-compulsive disorder (OCD) and/or its clinical features. To do so, 199 OCD patients and 201 healthy controls were genotyped using Polymerase Chain Reaction (PCR). Genotype distribution of both polymorphisms was in Hardy-Weinberg equilibrium. Although OCD and controls did not differ in terms of polymorphisms distribution, we observed that the presence of 10R-allele protected men of having OCD (P = 0.03). We also observed a significant association between the presence of 10R and checking in women (P = 0.02; OR = 3.14; 95%CI 1.08-9.11), and between the 9/9 genotype and neutralization in men (P = 0.04; OR = 3.38; 95%CI 1.03-11.11). Finally, the T-allele of -839C/T was significantly associated with the "obsession" score (P = 0.02; OR = 2.66; 95%CI 1.15-6.13). Our results demonstrate an important influence of dopaminergic pathways, particularly DAT1 polymorphisms, in OCD.

Glutamate transporter gene polymorphisms and obsessive-compulsive disorder: A case-control association study.

The etiology of obsessive-compulsive disorder (OCD) is largely unknown, but family, twin, neuroimaging, and pharmacological studies suggest that glutamatergic system plays a significant role on its underlying pathophysiology. We performed an association analysis of six Single Nucleotide Polymorphisms (SNPs) within SLC1A1 gene (rs12682807, rs2075627, rs3780412, rs301443, rs301430, rs301434) in a group of 199 patients and 200 healthy controls. Symptom profiles were evaluated using the Florida Obsessive-Compulsive Inventory (FOCI) and the Obsessive-Compulsive Inventory-Revised (OCI-R). SNPs were analyzed by Taqman® methodology (Thermo Fisher, Brazil). The genotype distributions were in Hardy-Weinberg equilibrium. The A-A-G (rs301434-rs3780412-rs301443) haplotype was twice as common in OCD as in controls (P = 0.02). We also found significant differences between male patients and controls for rs301443 in a dominant model (P = 0.04) and a protective effect of GG genotype of rs2072657 in women (P = 0.02). Regarding clinical characteristics, the G-A (rs301434-rs3780412) haplotype was almost twice more common in patients with vs. without hoarding (P = 0.04). Further analyses showed significant associations between hoarding and rs301434 (P = 0.04) and rs3780412 (P = 0.04) in women, both in a dominant model. A dominant effect was also observed on ordering dimension for rs301434 (P = 0.01, in women) and rs301443 (P = 0.04). Finally, the rs2072657 showed a recessive effect on neutralization (P = 0.04) and checking (P = 0.03, in men). These preliminary results demonstrated that the SLC1A1 may contribute to some extent the susceptibility to OCD and its symptoms. However, additional studies are still needed.

Gene variations in PBX1, LMX1A and SLITRK1 are associated with obsessive-compulsive disorder and its clinical features.

Genetic factors probably influence OCD development and a current hypothesis proposes that genes involved in the development of the central nervous system (CNS) are related to OCD. The aim of this study was to analyze six Single Nucleotide Polymorphisms (SNPs) in five genes with functions related to neurodevelopment in OCD. A total of 203 patient and 203 control samples were genotyped using the TaqMan® methodology. Statistically significant associations between OCD and PBX1 (rs2275558) in total sample (P = 0.002) and in males (P = 0.0003) were observed. Concerning symptom dimensions, the expression of neutralization showed a statistical significant association with LMX1A (rs4657411, P = 0.004) in total sample. We also observed significant association between LMX1A (rs4657411) and washing dimension in females (P = 0.01). Additionally, SLITRK1 (rs9593835) was significantly associated with checking dimension in male patients (P = 0.04). Our results indicate an important influence of neurodevelopment genes in the OCD susceptibility. Additional studies with larger samples are needed to confirm these results.

Association analysis of SLC6A4 and HTR2A genes with obsessive-compulsive disorder: Influence of the STin2 polymorphism.

BACKGROUND: Obsessive-Compulsive Disorder (OCD) is a complex and chronic disorder characterized by recurrent thoughts and/or repetitive behaviors. Given the potent anti-obsessional effects of the so-called serotonin reuptake inhibitors, genes related to serotonergic system may be well implicated in the etiopathogenesis of OCD. The gene encoding the serotonin transporter (SLC6A4), which shows a variable number of tandem repeat (VNTR) polymorphism in intron 2 (STin2), have been previously associated with OCD. Additionally, the serotonin 2A receptor gene (HTR2A) has two polymorphisms (A-1438G - rs6311, and T102C - rs6313), which have also been overrepresented among OCD patients. Therefore, the aim of this study is to evaluate the association of these three polymorphisms with OCD, through the examination of potential sources of heterogeneity in previous studies including age of onset, sex and symptom dimensions. METHODS: Polymorphisms were genotyped by Polymerase Chain Reaction (PCR) in a sample of 203 OCD patients and 205 healthy controls from Brazil. RESULTS: Although we did not observe any statistically significant association between the HTR2A gene polymorphisms and OCD or its clinical features, SLC6A4 STin2 polymorphism was significantly more common among OCD patients as compared to health controls. Further, a significant association between the STin2.12 allele and OCD, as well as a dominant effect of the STin2.12 allele in OCD was seen. Of note, late-onset (>18years) OCD was significantly more often seen in association with homozygosis for STin2.12 allele. No significant associations were observed with different OCD symptom dimensions. CONCLUSION: Our results indicate an important influence of the STin2 polymorphism in OCD, but more studies are warranted to confirm these results.