Histological and behavioral research in bipolar disorder (BD) implicates structural abnormalities in the hippocampus. Brain-derived neurotrophic growth factor (BDNF) protein is associated with ...hippocampal development and plasticity, and in mood disorder pathophysiology. We tested the hypotheses that both the BDNF val66met polymorphism and BD diagnosis are associated with decreased hippocampus volume, and that individuals with BD who carry the met allele have the smallest hippocampus volumes compared to individuals without BD and val/val homozygotes. We further explored localization of morphological differences within hippocampus in BD associated with the met allele. Twenty individuals with BD and 18 healthy comparison (HC) subjects participated in high-resolution magnetic resonance imaging scans from which hippocampus volumes were defined and measured. We used linear mixed model analysis to study effects of diagnosis and BDNF genotype on hippocampus volumes. We then employed three-dimensional mapping to localize areas of change within the hippocampus associated with the BDNF met allele in BD. We found that hippocampus volumes were significantly smaller in BD compared to HC subjects, and presence of the BDNF met allele was associated with smaller hippocampus volume in both diagnostic groups. The BD subgroup who carried the BDNF met allele had the smallest hippocampus volumes, and three-dimensional mapping identified these decreases as most prominent in left anterior hippocampus. These results support effects of BD diagnosis and BDNF genotype on hippocampus structure and suggest a genetic subgroup within BD who may be most vulnerable to deficits in hippocampus and may most benefit from interventions that influence BDNF-mediated signaling.
Abstract Male bonnet monkeys ( Macaca radiata ) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and ...behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
We recently reported that, in a European-American (EA) sample, the interaction between two cannabinoid receptor 1 gene (CNR1) variants significantly increased risk for drug dependence (DD), including ...cocaine dependence (CD). This study aimed to investigate directly the association between CNR1 and CD in four independent samples. Eight markers across the 45 kb CNR1 region and four large samples, ie, family-based European-American (EA) sample (n=734), case-control EA sample (n=862), family-based African-American (AA) sample (n=834) and case-control AA sample (n=619) were examined in the present study. We investigated the association of these markers with CD and cocaine-induced paranoia (CIP) in the EA family sample first, and then replicated positive results in the other three samples. The interaction between two independent CNR1 variants, ie, the G allele-containing genotypes of rs6454674 (SNP3(G+)), and the T/T genotype of rs806368 (SNP8(T)/T), significantly increased risk for CD in the EA family (P(GEE)=0.015) and EA case-control (P(regression)=0.003) samples. EA subjects with SNP3(G+) and SNP8(T)/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs (LR+ =1.4). The SNP3(G)-SNP8(T)haplotype also showed significant association (P=0.018) with CD in the EA case-control sample. SNP8-containing haplotypes showed significant association with both CD (P(global)=0.007) and CIP (P(global)=0.003) in the EA family sample. In the AA family sample, SNP8(T)/T significantly conferred higher risk for CD (P=0.019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs.
The kidney and brain expressed protein gene (KIBRA) and the calsyntenin 2 gene (CLSTN2) are reportedly involved in synaptic plasticity. Single nucleotide polymorphisms (SNPs) rs17070145 (KIBRA) and ...rs6439886 (CLSTN2) have been found to affect memory performance measures. This study examined the association of KIBRA SNP rs17070145 and CLSTN2 SNPs rs6439886 and rs17348572 (a nonsynonymous variant) with cognitive flexibility in 674 African Americans (AAs; 526 current smokers) and 419 European Americans (EAs; 318 current smokers). The subjects' cognitive flexibility was assessed using the Wisconsin Card Sorting Test. The effects on cognitive flexibility of sex, age, education, and tobacco recency (a possible mediator of gene effects in smokers), the three SNPs, and the interaction of each SNP with tobacco recency were analyzed using multivariate analysis of variance. In AAs, there were no main or interaction effects of the SNPs on cognitive flexibility. In EAs, the two CLSTN2 SNPs showed no main effect on cognitive flexibility. However, among EAs, individuals with the KIBRA rs17070145 T allele made significantly more perseverative responses (P=0.002) and perseverative errors (P=0.002) than those with no T allele. Furthermore, among EAs with the rs17070145 T allele, current smokers made significantly fewer perseverative responses (P<0.001) and perseverative errors (P<0.001) than past smokers. Nongenetic factors (age, education, and tobacco recency) had substantial effects on cognitive flexibility in both AAs and EAs. We conclude that variation in KIBRA influences cognitive flexibility in a population-specific way, and that current smoking status moderates this effect.
Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk ...factor for a variety of psychopathologic conditions including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample.
Study participants 602 European-Americans (EAs) and 779 African-Americans (AAs) were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Triallelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group.
There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S' allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR×ACE interaction. However, among European-Americans, male sex (odds ratio=3.36; P<0.001) and ACE history (odds ratio=1.47; P=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex×5-HTTLPR genotype×ACEs (χ=13.92, P<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, whereas among AA women, the effect of ACEs on ASPD was significant only among S' homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S'S' genotype; N=7) and require replication.
Childhood maltreatment contributes to the risk of ASPD, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.
The N‐methyl‐D‐aspartate (NMDA) glutamate receptors play important roles in the pathophysiology of substance dependence (SD), but no strong genetic evidence has associated common variants in ...NMDAR‐related genes to SD. We hypothesized that rare variants (RVs) with minor allele frequency <1% in the NMDAR‐related genes might exert large effects on SD risk. We sequenced 34 544 bp of coding and flanking intronic regions of 17 genes involved in the NMDA system in 760 subjects, all with co‐occurring alcohol dependence, cocaine dependence and opioid dependence (OD), and 760 healthy control subjects. One hundred percent of the target regions were sequenced at >1000× coverage. We identified 454 variants, including 380 RVs. Based on case‐control allele count differences, we genotyped 11 exonic RVs in 6751 additional subjects, and the 1520 subjects from the sequencing stage for validation. All alleles of the 11 RVs called in the sequencing stage were confirmed. We found a statistically significant association of the 11 RVs with OD in African Americans (P = 0.00080). Results from gene‐based association tests showed that the association signal derived mostly from DISC1 (P = 0.0010) and GRIN2B (P = 0.00085). DISC1 is a well‐validated schizophrenia risk gene. This is the first demonstration that RVs affect the risk of OD and the first demonstration of biological convergence of schizophrenia and OD risk—via DISC1.
The N‐methyl‐D‐aspartate (NMDA) glutamate receptors play important roles in the pathophysiology of substance dependence (SD), but no strong genetic evidence has associated common variants in NMDAR‐related genes to SD. We hypothesized that rare variants (RVs) with minor allele frequency < 1% in the NMDAR‐related genes might exert large effects on SD risk. We sequenced 34,544 bp of coding and flanking intronic regions of 17 genes involved in the NMDA system in 760 subjects, all with co‐occurring alcohol dependence (AD), cocaine dependence (CD) and opioid dependence (OD), and 760 healthy control subjects. One hundred percent of the target regions were sequenced at > 1000× coverage. We identified 454 variants, including 380 RVs. Based on case‐control allele count differences, we then genotyped 11 exonic RVs in 6751 additional subjects, and the 1520 subjects from the sequencing stage for validation. We found a statistically significant association of the 11 RVs with OD in AAs (P=0.00080). Results from gene‐based association tests showed that the association signal derived mostly from DISC1 (P=0.0010) and GRIN2B (P=0.00085). DISC1 is well‐validated as affecting cognitive function. This is the first demonstration that RVs affect the risk of OD and the first demonstration of biological convergence of schizophrenia and OD risk – via DISC1.
Genetic risk variants for social anxiety Stein, Murray B.; Chen, Chia‐Yen; Jain, Sonia ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
June 2017, 2017-Jun, 2017-06-00, 20170601, Letnik:
174, Številka:
4
Journal Article
Tobacco smoking leads to increased numbers of β2*-containing nicotinic acetylcholine receptors (β2*-nAChRs) throughout the brain, which return to nonsmoker levels over extended abstinence. The goal ...of the current study was to determine whether the degree of tobacco smoking-induced changes in β2*-nAChR availability is genetically influenced.
In this study, 113 European Americans participated in one or two (123)I5-IA-85380 single photon emission computed tomography (SPECT) brain scans. Smokers (n = 58) participated in one scan at 7-9 days of abstinence and those who remained abstinent (n = 27) were imaged again at 6-8 weeks of abstinence. Age- and sex-matched nonsmokers (n = 55) participated in one scan. Blood samples were collected for DNA analysis and genotyped for single nucleotide polymorphisms (SNPs) in the CHRNA4 and ANKK1 gene loci. β2*-nAChR availability was measured in the thalamus, striatum, cortical regions, and cerebellum.
The CHRNA4 SNP rs2236196 and ANKK1 SNP rs4938015 were associated with significantly higher cerebellar and cortical β2*-nAChR availability in smokers versus nonsmokers for specific genotypes. There were no significant differences by carrier status in the change in β2*-nAChR availability in smokers from 7-9 days to 6-8 weeks of abstinence.
This study provides evidence for genetic regulation of tobacco smoking-induced changes in β2*-nAChR availability and suggests that β2*-nAChR availability could be an endophenotype mediating influences of CHRNA4 variants on nicotine dependence. These results highlight individual differences in the neurochemistry of nicotine dependence and may suggest the need for individualized programs for smoking cessation.
This study demonstrates genetic regulation of smoking-induced changes in β2*-nAChRs throughout the brain and highlights the need for personalized programs for smoking cessation.
Prior research has shown that most known risk factors for suicide attempts in the general population actually predict suicide ideation rather than attempts among ideators. Yet clinical interest in ...predicting suicide attempts often involves the evaluation of risk among patients with ideation. We examined a number of characteristics of suicidal thoughts hypothesized to predict incident attempts in a retrospective analysis of lifetime ideators (N = 3,916) drawn from a large (N = 29,982), representative sample of United States Army soldiers. The most powerful predictors of first nonfatal lifetime suicide attempt in a multivariate model controlling for previously known predictors (e.g., demographics, mental disorders) were: recent onset of ideation, presence and recent onset of a suicide plan, low controllability of suicidal thoughts, extreme risk-taking or "tempting fate," and failure to answer questions about the characteristics of one's suicidal thoughts. A predictive model using these risk factors had strong accuracy (area under the curve AUC = .93), with 66.2% of all incident suicide attempts occurring among the 5% of soldiers with highest composite predicted risk. This high concentration of risk in this retrospective study suggests that a useful clinical decision support model could be constructed from prospective data to identify those with highest risk of subsequent suicide attempt.
General Scientific Summary
Suicide is a leading cause of death worldwide. One of the greatest challenges in this area is predicting which people who think about suicide will act on those thoughts and make a suicide attempt. In this study, we documented several characteristics of suicide-related thoughts that predict incident nonfatal suicide attempts with good accuracy.
The alcohol dehydrogenase (ADH) family constitutes one of the key sets of enzymes responsible for the oxidation of alcohol. The ADH4 gene, an important member of this family, is a functional and ...positional candidate for alcohol dependence. The present study aimed to investigate the relationship between ADH4 gene variation and alcohol dependence and drug dependence in European-Americans (EAs) and African-Americans (AAs). Seven single nucleotide polymorphisms (SNPs) spanning the ADH4 gene were genotyped in 365 healthy controls (317 EAs and 48 AAs) and 561 subjects (400 EAs and 161 AAs) affected with alcohol dependence and/or drug dependence (436 with alcohol dependence; 356 with drug dependence). Hardy-Weinberg equilibrium (HWE) for the genotype frequency distributions of these markers was tested in all phenotype groups to evaluate association between ADH4 gene variation and phenotypes and to fine-map the disease risk locus. The allele, genotype, and haplotype frequency distributions of these markers were compared between cases and controls to confirm the associations. The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy-Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases. Among all markers, SNP2 (rs1042363) at exon 9 or SNP6 (rs1800759) at the promoter showed the greatest degree of HWD, among patients with either alcohol dependence or drug dependence. Significant differences between EA cases and controls were seen for genotype (10(-6)<global p<0.044), but not any allele or haplotype, frequency distributions for all seven ADH4 markers. These findings suggest that ADH4 genotypes predispose to alcohol dependence and drug dependence in a recessive manner, a predisposition that is population specific. SNP2 or SNP6 was the marker genetically closest to the functional risk loci for both alcohol dependence and drug dependence.
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