COMT Rs4680 Research Articles

P.3.004 - Neuropsychological correlates of ADRA2A(rs1800544) and COMT(rs4680) polymorphisms in Turkish ADHD patients

Introduction The complex etiology of ADHD has a strong genetic component. ADRA2A (rs1800544) and COMT (rs4680) polymorphisms are two of the most studied gene polymorphisms in ADHD etiology. However, there is still debate about their indication ofcreating different neuropsychological phenotypes in ADHD.In this study, we aimed to investigate the effects of these polymorphisms on neuropsychological traits among Turkish ADHD patients. Also, the relationship between ADHD symptoms, subtypes and neuropsychological test variables were studied. Methods To examine the phenotypic discrepencies of these genotypes, Continuous Performance Test(CPT) and Trail Making Tests (TMTA-TMTB) were conducted for 121 genotyped ADHD patients between 6-18 years old. Omission- commission errors and mean response time were used as CPT variables. Besides this, completing times, errors and corrections were the variables recorded for TMTA and TMTB. Mental retardation was excluded with Wechsler Intelligence Scale for Children-4 (WISC4)/Wechsler Intelligence Scale for Children –Revised (WISC-R) in the study. Diagnosis and subtype discrimination were confirmed and comorbidities except learning and disruptive behaviour disorders were excluded by using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Clinical Global Impression –Severity Scale (CGI-S) documented clinical severity, whereas Global Assesment of Functioning Scale (GAS) stated clinical functionality. Conners’ Parent (CPRS) and Teacher Rating Scales (CTRS) were used for determining ADHD symptoms and severity. The statistical analyses were conducted with SPSS 21.0. Mann-Whitney U, Kruskal–Wallis, Spearman correlation tests were used and p Results No relationship was detected between ADRA2A,COMT polymorphisms and CPT,TMT variables. CPT commission errors were found more frequent in the combined subtype, while TMTA corrections were more seen in the inattentive subtype.The learning problem subscale of CPRS and hyperactivity, behaviour problem subscales of CTRS were found associated with CPT commission errors. The hyperactivity, oppositional behaviour subscales of CPRS were related to TMTA errors and corrections whereas behaviour problem subscale of CPRS was only associated with TMTA corrections. The hyperactivity and behaviour problem subscales of CTRS were found correlated with TMTA completing time, errors and corrections. Only attention deficiency subscale of CTRS was found associated both with TMTA corrections and TMTB completing time and errors. CPT parameters were found associated with neither clinical severity nor functioning.However, low clinical functionality ( Conclusions ADRA2A and COMT polymorphisms were not found to be associated with a specific neuropsychological phenotype. While CPT did not predict clinical severity or functioning, longer TMT completing time and more TMT corrections were found associated with lower functionality. Although the results of neuropsychological tests were in accordance with ADHD subtypes, neuropsychological traits did not differ in a homogeneous manner in ADHD patients. Consequently, instead of using the neuropsychological traits in distinguishing groups, they may be helpfully used for supporting clinical evaluation in ADHD. In addition, further studies with whole genome sequencing technics are warrented to better understand the role of polymorphisms in ADHD etiology.

Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response

Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10−8). These results imply that PPI might be modulated by four genotypes – COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 – indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is – like the disease phenotype – highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.

The association between COMT rs4680 and OPRM1 rs1799971 polymorphisms and temperamental traits in combat athletes

The aim of this study is to analyse associations between functional polymorphisms in the COMT and OPRM1 genes and temperamental traits in athletes.The study involved 364 healthy men, aged 18 to 43years. 199 combat athletes participated in the experimental group. The control group consisted of 165 healthy men. All subjects were genotyped for common variants of the COMT and OPRM1 genes, and were included in a case-control study.Temperament was measured with the Formal Characteristics of Behaviour – Temperament Inventory (FCB-TI).The scores for temperament traits obtained by the athletes were lower with regard to perseveration and emotional reactivity, and higher with regard to endurance, when compared to the control group.When analysing the OPRM1 rs1799971 genotype in relation to temperamental traits, athletes carrying at least one minor G allele were characterized by higher sensitivity when compared with AA wild-type homozygotes. However, such an association was not observed in the controls. In the case of the COMT rs4680 variant studied, among the athletes, homozygous GG subjects were characterized by lower sensitivity, compared to the A allele carriers. On the other hand, AA homozygotes presented lower endurance than G allele carriers.

Investigation of the COMT Val158Met variant association with age of onset of psychosis, adjusting for cannabis use.

Objective COMT rs4680 (Val158Met) genotype moderates the effect of cannabis on the age of onset of psychosis (AoP). We investigated the association between rs4680 and AoP, after adjusting for relevant covariates, in a Canadian Caucasian sample.MethodsOne hundred and sixty‐nine subjects with psychosis were recruited. AoP, defined as age of DSM‐IV diagnosis was established using the Structured Clinical Interview for DSM‐IV. Cannabis use data were collected using a self‐report computerized questionnaire. DNA was extracted from saliva and genotyping of the COMT Val158Met polymorphism was done by SNaPshot and TaqMan assays. Logistic regression and Kaplan–Meier analysis results are reported.ResultsIn those who had used cannabis before 20 years of age, rs4680 had a trend level effect on AoP (median AoP: Val/Val < Val/Met < Met/Met 19.37, 20.95, 21.24 years, respectively; log‐rank test p = .051).ConclusionOur data are indicative of the need to further investigate the association between the COMT rs4680 variant and AoP in the context of adolescent cannabis use.

The significance of polymorphism and expression of oestrogen metabolism-related genes in Chinese women with premature ovarian insufficiency

The aim of this study was to investigate whether polymorphism and expression of CYP17, CYP1A1, COMT and SULT1A1 affected the risk of idiopathic primary ovarian insufficiency (POI) in Chinese women. DNA sequencing and real-time PCR were used to detect these genes in 132 cases of idiopathic POI and 132 normal women. A significant increase in the C allele of CYP17 (rs743572) polymorphism was observed in women with POI compared with controls (PFDR = 0.046). A significant decrease was observed in the C allele of CYP1A1 (rs4646903) in women with POI compared with controls (PFDR = 0.004). The A allele of COMT (rs4680) polymorphism was more frequent in women with POI compared with controls (PFDR = 0.029). The genotypic frequency of SULT1A1 (rs9282861) was not significantly different between the two groups. For the relative expression of CYP17 and COMT were statistically significant (both PFDR = 0.066), with false discovery rate controlled at 0.1. No significant difference was observed in the RNA levels of CYP1A1 and SULT1A1 between the two groups. The frequency of expression of the CYP17 T/C variant tended to be higher and the A allele of COMT polymorphism together with down-regulation of its mRNA expression may be more frequent in Chinese women with idiopathic POI.

Abstract 1274: Associations between genetic polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial

Abstract Background: Substantial preclinical data corroborate the critical role of estrogen in prostate cancer development; however, epidemiological studies found no associations between circulating estrogen levels and prostate cancer risk. It was hypothesized that intraprostatic estrogen milieu may play a more important role than circulating estrogen in prostate carcinogenesis. Since it is difficult to obtain data on prostatic estrogen levels, we tested the hypothesis indirectly by investigating associations of prostate cancer risk with genetic variations of enzymes that are involved in estrogen synthesis, metabolism and function, and may affect intraprostatic estrogen milieu. Methods: A panel of 36 potentially functional single nucleotide polymorphisms (SNPs) in estrogen-related genes was assembled based on information obtained in the literature. After removing SNPs with call rate &amp;lt;95% (1 SNP) or minor allele frequency &amp;lt;3% (10 SNPs), a total of 25 SNPs in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined for associations with prostate cancer risk using data and DNA samples from 1617 cases and 1731 controls in the Prostate Cancer Prevention Trial (PCPT). Cases and controls were frequency-matched on age, treatment arm and family history. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately in the placebo and finasteride arms, adjusting for age, race and family history. Results were similar when restricting analysis to white men only. Results: Panels of SNPs that were significantly associated with prostate cancer risk were different according to treatment arm, showing rs1801132 in ESR1, rs700518 in CYP19A1, and rs4124874 in UGT1A6 in the placebo arm and rs2445765 in CYP19A1 and rs4680 in COMT in the finasteride arm. When stratified by circulating estrogen and androgen levels, significant associations were only observed in either the high or low category of serum hormone levels; no SNPs were significantly associated with prostate cancer risk in both categories. CYP19A1 was the only gene harboring SNPs that were significantly associated with prostate cancer risk in both the placebo (rs700518) and finasteride arms (rs2445765). In haplotype analysis using all three CYP19A1 SNPs genotyped in the study (rs700518, rs2445765 and rs700519), compared with non-risk haplotype (GCC), certain CYP19A1 haplotypes were significantly associated with increased prostate cancer risk in both arms. Conclusion: Associations between prostate cancer risk and SNPs in genes involved in estrogen metabolism and function are complicated, and markedly modified by other factors such as finasteride treatment or circulating hormone levels. Supported by grant U10CA37429, 5UM1CA182883 and P01CA108964 from the NCI. Citation Format: Li Tang, Mary Platek, Song Yao, Cathee Till, Phyllis Goodman, Catherine M. Tangen, Yue Wu, Elizabeth A. Platz, Marian L. Neuhouse, Frank Z. Stanczyk, Juergen K. Reichardt, Regina M. Santella, Ann Hsing, William D. Figg, Scott M. Lippman, Ian M. Thompson, Christine B. Ambrosone. Associations between genetic polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1274. doi:10.1158/1538-7445.AM2017-1274

Associations of endocrine stress-related gene polymorphisms with risk of autism spectrum disorders: Evidence from an integrated meta-analysis.

Our results showed no evidence of significant association of either COMT rs4680 or 5-HTT 5-HTTLPR variants with ASD, showing that these two genes may not be major susceptible genetic factors in ASD occurrence, and may have a reciprocal action with each other in combination with environmental factors. These findings further provide evidence that a single gene variant may not dictate autism occurrence, but possibly contributes to a specific phenotype or subtype of ASD.

The influence of CHRNA4, COMT, and maternal sensitivity on orienting and executive attention in 6-month-old infants

Despite claims concerning biological mechanisms sub-serving infant attention, little experimental work examines its underpinnings. This study examines how candidate polymorphisms from the cholinergic (CHRNA4 rs1044396) and dopaminergic (COMT rs4680) systems, respectively indicative of parietal and prefrontal/anterior cingulate involvement, are related to 6-month-olds’ (n=217) performance during a visual expectation eye-tracking paradigm. As previous studies suggest that both cholinergic and dopaminergic genes may influence susceptibility to the influence of other genetic and environmental factors, we further examined whether these candidate genes interact with one another and/or with early caregiving experience in predicting infants’ visual attention. We detected an interaction between CHRNA4 genotype and observed maternal sensitivity upon infants’ orienting to random stimuli and a CHRNA4-COMT interaction effect upon infants’ orienting to patterned stimuli. Consistent with adult research, we observed a direct effect of COMT genotype on anticipatory looking to patterned stimuli. Findings suggest that CHRNA4 genotype may influence susceptibility to other attention-related factors in infancy. These interactions may account for the inability to establish a link between CHRNA4 and orienting in infant research to date, despite developmental theorizing suggesting otherwise. Moreover, findings suggest that by 6months, dopamine, and relatedly, the prefrontal cortex/anterior cingulate, may be important to infant attention.

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease.

The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study’s objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

Genetic Influences of OPRM1,OPRD1 and COMT on Morphine Analgesia in a Multi‐Modal, Multi‐Tissue Human Experimental Pain Model

Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models.

ZNF804A rs1344706 interacts with COMT rs4680 to affect prefrontal volume in healthy adults.

The biological function of ZNF804A rs1344706, the first genome-wide supported risk variant of schizophrenia, remains largely unknown. Based on the upregulating effect of ZNF804A on the expression of COMT, we hypothesize that ZNF804A may affect grey matter volume (GMV) by interacting with COMT. Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects. The GMV of the left dorsolateral prefrontal cortex (DLPFC) showed a significant COMT rs4680×ZNF804A rs1344706 interaction, manifesting as an inverted U-shape modulation by the presumed dopamine signaling. In COMT Met-allele carriers, the ZNF804A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes. In COMT Val/Val homozygotes, however, the ZNF804A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes. These findings suggest that ZNF804A affects the GMV of the prefrontal cortex by interacting with COMT, which may improve our understanding of neurobiological effect of ZNF804A and its association with schizophrenia.

Polymorphisms of catechol-O-methyltransferase ( COMT rs4680:G&gt;A ) and μ-opioid receptor ( OPRM1 rs1799971:A &gt;G ) in relation to pain perception in combat athletes

Polymorphisms of catechol-O-methyltransferase ( COMT rs4680:G&gt;A ) and μ-opioid receptor ( OPRM1 rs1799971:A &gt;G ) in relation to pain perception in combat athletes

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Alcohol dependence (AD), associated with high mortality and morbidity is caused due to involvement of both environmental and genetic factors. Behavioral effects of alcohol including cognitive impairment, motor incoordination, tolerance and dependence are likely due to its effect on the multiple brain proteins including neurotransmitters. Dysfunction in these neurotransmitter systems may be at the level of enzymes involved in metabolic degradation, or receptors involved in neurotransmission like dopamine, Gamma-amino butyric acid (GABA), serotonin etc. Genetic polymorphisms in these neurotransmitter systems are implicated in conferring susceptibility to AD. Aim: To identify association of single nucleotide polymorphisms (SNPs) in COMT (rs4680 and rs2075507) and GABAA receptor genes (rs13172914 and rs211014) with AD. Method: A total of 100 AD patients diagnosed on the basis of DSM IV criteria from the outpatient clinic of the National Drug Dependence Treatment Centre (NDDTC) of All India Institute of Medical Sciences (AIIMS), and 100 healthy individuals from the general population were recruited. A detailed history including pattern of drug use and demographic details with pedigree information was noted. Genomic DNA from peripheral blood samples was processed for PCR amplification followed by restriction digestion to screen for the presence of polymorphisms. Genotype and allele frequencies were evaluated and correlated with alcohol use parameters including duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and WHO ASSIST score and levels of liver function enzymes (SGPT and SGOT). Statistical analysis was performed using SPSS v21.0. Results: Genetic analysis of the study group revealed COMT rs4680 to be significantly associated with AD (p=0.03), while the other COMT SNP rs2075507 showed an association with increased levels of SGPT in the patients. GABAA receptor gene polymorphisms showed no association with AD. Conclusion: The study suggests a role of COMT gene polymorphism rs4680 in conferring susceptibility to AD.

M52 - Association of СОМТ, DRD2, MTHFR, MIR-137, DNMT3B Polymorphisms with Cognitive Functioning and Symptom Severity of Schizophrenia Patients

Background Schizophrenia is a complex disorder with a high heterogeneity of its clinical implications. A lot of studies analyzing polymorphisms of potential schizophrenia candidate genes give inconsistent results. It may be related to ethnic factor, differences in sample size, but also with inhomogeneity of samples regarding clinical characteristics. In an attempt to receive more reproducible results we made thorough sample selection to homogeneous groups according to the dominant manifestation of schizophrenia symptoms, cognitive defects and other disease aspects. Methods Five gene polymorphisms: rs1801133 of MTHFR, rs4680 of СОМТ, rs1625579 of Mir-137, rs2424913 of DNMT3b were analyzed for 142 schizophrenia patients and 91controls (Belarusian population) by RFLP and TaqMan probes. Symptom severity was evaluated with the help of PANSS rating criteria, cognitive functioning - by using WTSC. Chi square, Mann-Whitney, Kruskal-Wallis tests were used for the association of gene loci with schizophrenia, severity of symptoms and cognitive functioning of patients. Results Analysis of the data revealed: 1) No direct association of any investigated loci with risk of developing schizophrenia. 2) There is an association of MTHFR and Mir-137 loci with total index of positive items of PANSS as well as of Mir-137 with general psychopathology and overall performance of all subscales for all patients (males and females). Remarkably, we have found an association of Mir-137 with total index of negative items and overall performance of all subscales for females only. 3) There is an association of COMT rs4680 with total index of negative items, general psychopathology and overall performance of all subscales. Such result is observed only for males. 4) There is an association of COMT rs4680 with variables of WTSC: percentage of nonperseverative errors, the number of cards used within the test, the number of completed categories, the number of trials to complete the first category. 5) There is an association of DNMT3b locus with total index of general psychopathology symptoms and overall performance of all subscales only for females. Discussion We conclude: • Both rs1801133 of MTHFR and rs1625579 of Mir-137 are involved in the mechanism of formation of positive syndrome for all patients, but the effects are observed only in the combined sample (males + females). • COMT rs4680 is involved in the formation of the negative syndrome and general psychopathology symptoms for all patients, but for males is much stronger. A significant impact on the negative syndrome formation among females is observed for rs1625579 of Mir-137. • Rs4680 of COMT and rs1625579 of Mir-137 are associated with the wide range of pathological processes in schizophrenia for all patients, but the effect of the COMT gene is stronger for males, and Mir-137 gene - for females. Moreover, rs2424913 of DNMT3b shows a significant influence on the general psychopathology symptoms and overall symptomology of disease pattern for females. • COMT is associated with cognitive functioning of patients with schizophrenia. The obtained results indicate that investigated factors have gender-specific impacts on symptoms and syndromes and confirm the differences in the mechanisms of pathogenesis of schizophrenia between males and females.

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs.

Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023). Wider application of WES will help to determine the effects of mutations on the activities of proteins encoded by drug response genes, and the information gained will accelerate the development of personalized therapies for patients with cancer. Moreover, this knowledge may provide clues for preventing cancer before the onset of symptoms.

Genes associated with persistent lumbar radicular pain; a systematic review.

BackgroundThe aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients.MethodsThe search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality.ResultsThe search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1α rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFα, IL6 and IFNα, were associated with persistent LRP.ConclusionThe present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary.Trial registrationThe review is registered PROSPERO 20th of November 2015. Registration number is CRD42015029125.

A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex.

With evidence of sexual dimorphism involving the dopamine (DA)-pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex × DA-gene interactions may influence cognition post-TBI. Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center. Risk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches. A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains. A significant sex × gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P = .002, 12M: P = .001) and COMT rs4680 (6M: P = .048; 12M: P = .004); DRD2 rs6279 (P = .001) and VMAT rs363226 (P = .043) genotypes were independently associated with cognition at 6 months, with trends for a sex × gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R = 0.344 (6 months); R = 0.441 (12 months), significantly increasing the variance captured from the base prediction models. A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention.

The COMT rs4680 polymorphism and suicide attempt in rural Shandong, China.

Suicide attempt is a major public health problem and are associated with genetic factors. This paired case-control study examined the association between the COMT gene rs4680 polymorphism and suicide attempts. A case-control study of 369 (117 men, 31.7%; mean age=44.1±13.3 years) suicide attempters and an equal number of controls without a lifetime history of suicide attempt matched on sex, age, and residence was carried out in rural Shandong, Eastern China. Demographics and psychiatric history were obtained through face-to-face interviews. Blood samples were collected during interviews and the COMT gene rs4680 polymorphism was analyzed using the ligation detection reaction method. The G/G genotype was significantly more prevalent in female suicide attempters than their matched controls. Conditional logistic regression showed that the G/G genotype was significantly associated with an increased risk of suicide attempts only for women (odds ratio=2.3; 95% confidence interval: 1.2-4.2). The findings support an association between the COMT gene rs4680 polymorphism and suicide attempts only in women. Further research with larger samples is needed to explore the interactions of the COMT gene rs4680 polymorphism and sex and psychiatric disorders on suicide attempts.

Ethnicity-dependent influence of innate immune genetic markers on morphine PCA requirements and adverse effects in postoperative pain.

Although several genetic factors have been associated with postsurgical morphine requirements, those involving the innate immune system and cytokines have not been well investigated. The aim of this study was to investigate the contribution of genetic variability in innate immune signalling pathways to variability in morphine dosage after elective caesarean section under spinal anaesthesia in 133 Indian, 230 Malay, and 598 Han Chinese women previously studied. Twenty single nucleotide polymorphisms in 14 genes involved in glial activation (TLR2, TLR4, MYD88, MD2), inflammatory signalling (IL2, IL6, IL10, IL1B, IL6R, TNFA, TGFB1, CRP, CASP1), and neuronal regulation (BDNF) were newly investigated, in addition to OPRM1, COMT, and ABCB1 genetic variability identified previously. Postsurgical patient-controlled analgesia morphine use (mg/24 hours) was binned into 6 normally distributed groups and scored 0 to 5 to facilitate step-down multiple linear regression analysis of genetic predictors, controlling for ethnicity and nongenetic variables. Ethnicity, OPRM1 rs1799971 (increased), TLR2 rs3804100 (decreased), and an interaction between ethnicity and IL1B rs1143634 (increased), predicted 9.8% of variability in morphine use scores in the entire cohort. In the Indian cohort, 14.5% of the variance in morphine use score was explained by IL1B rs1143634 (increased) and TGFB1 rs1800469 (decreased). In Chinese patients, the incidence of postsurgical pain was significantly higher in variant COMT rs4680 genotypes (P = 0.0007) but not in the Malay or Indian cohorts. Innate immune genetics may contribute to variability in postsurgical opioid requirements in an ethnicity-dependent manner.

COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis.

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (β = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.