Xian-Zhang Hu

Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder

A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.

An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk.

BACKGROUND Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. One such intermediate phenotype is the low level of response (LR) to alcohol. This project used a case-control approach to search for genes that may contribute to LR. METHODS Data were available from alcohol challenges at approximately age 20 and regarding the development of alcohol use disorders over the subsequent 20 years for 85 men, including 40 reported in a previous genetic analysis. LR was evaluated using oral consumption of 0.75 ml/kg of alcohol, after which changes in subjective feelings of intoxication and body sway were measured. Alcohol abuse and dependence were diagnosed by DSM-III-R criteria through structured interviews administered to both the participant and an informant (usually the spouse) 10, 15, and 20 years after initial testing. Four polymorphisms were evaluated, including the serotonin transporter HTTLPR promoter ins/del, GABAAalpha6 Pro385Ser, NPY Leu7Pro, and catalase 262C>T. Two of these, HTTLPR and GABAAalpha6 Pro385Ser, had been previously associated with LR and alcoholism in a preliminary study. RESULTS The HTTLPR L allele was significantly related to both the LR and alcoholism in an allele-dosage (stepwise) manner. Furthermore, the association remained when L alleles were subdivided into recently reported functional subtypes: the lowest LR was associated with genotypes correlated with the highest serotonin transporter expression. The GABAAalpha6 Ser385 allele showed a nonsignificant trend for association to a low LR, as had been previously observed, although the Ser385 allele is uncommon, and only 18 heterozygotes were in the current group. However, the six men with both LL and Pro385/Ser385 genotypes had the lowest LR, and each had developed alcoholism during follow-up. Neither NPY nor catalase was associated with either LR or alcoholic outcomes, although the sample did not have sufficient power for definitive conclusions. CONCLUSIONS This report strengthens the support for a relationship between the HTTLPR L and GABAAalpha6 Ser385 alleles to low alcohol LR and to alcoholism in a prospectively studied cohort evaluated for LR in young adulthood and before the onset of alcohol dependence.

Genetic variation in human NPY expression affects stress response and emotion.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Interaction between Childhood Trauma and Serotonin Transporter Gene Variation in Suicide

Although the serotonin transporter promoter polymorphism (5-HTTLPR) contributes to depression and suicidality in a fashion modulated by environmental stress, 5-HTTLPR has been little examined in relation to suicidal behavior in substance dependence. Recently, a third functional allele of 5-HTTLPR was discovered enabling more of the interindividual variation in serotonin transporter expression to be predicted by genotype. We examined whether the 5-HTTLPR gene alone, or interacting with childhood trauma, was predictive of suicidal behavior in substance-dependent patients, a clinical population that is at high risk of suicide, as well as childhood trauma and other stress. We interviewed 306 abstinent male African-American substance-dependent patients about whether they had ever attempted suicide and administered the 34-item Childhood Trauma Questionnaire (CTQ). Patients and 132 male African-American controls were genotyped to determine the S, LG, and LA 5-HTTLPR alleles; some analyses grouped the S and LG alleles on the basis of equivalent function. The distribution of 5-HTTLPR genotypes did not differ between patients and controls, nor between suicide attempters and non-attempters. However, patients with low expression 5-HTTLPR genotypes and above-median CTQ scores were more likely to have attempted suicide. Logistic regression showed increasing risk of a suicide attempt with increasing reports of childhood trauma scores; in addition, this increase was exaggerated among those with low expression forms of the 5-HTTLPR genotype. Childhood trauma interacts with low expressing 5-HTTLPR genotypes to increase the risk of suicidal behavior among patients with substance dependence.

Subchronic alpha-linolenic acid treatment enhances brain plasticity and exerts an antidepressant effect: a versatile potential therapy for stroke.

Omega-3 polyunsaturated fatty acids are known to have therapeutic potential in several neurological and psychiatric disorders. However, the molecular mechanisms of action underlying these effects are not well elucidated. We previously showed that alpha-linolenic acid (ALA) reduced ischemic brain damage after a single treatment. To follow-up this finding, we investigated whether subchronic ALA treatment promoted neuronal plasticity. Three sequential injections with a neuroprotective dose of ALA increased neurogenesis and expression of key proteins involved in synaptic functions, namely, synaptophysin-1, VAMP-2, and SNAP-25, as well as proteins supporting glutamatergic neurotransmission, namely, V-GLUT1 and V-GLUT2. These effects were correlated with an increase in brain-derived neurotrophic factor (BDNF) protein levels, both in vitro using neural stem cells and hippocampal cultures and in vivo, after subchronic ALA treatment. Given that BDNF has antidepressant activity, this led us to test whether subchronic ALA treatment could produce antidepressant-like behavior. ALA-treated mice had significantly reduced measures of depressive-like behavior compared with vehicle-treated animals, suggesting another aspect of ALA treatment that could stimulate functional stroke recovery by potentially combining acute neuroprotection with long-term repair/compensatory plasticity. Indeed, three sequential injections of ALA enhanced protection, either as a pretreatment, wherein it reduced post-ischemic infarct volume 24 h after a 1-hour occlusion of the middle cerebral artery or as post-treatment therapy, wherein it augmented animal survival rates by threefold 10 days after ischemia.

Effects of stressful life events, maternal depression and 5-HTTLPR genotype on emotional symptoms in pre-adolescent children

There has been a large but inconsistent literature on interactions between the 5‐HTTLPR polymorphism of the serotonin transporter gene and adversity on emotional disorders. We investigated these interactions in 4,334 children from a birth longitudinal cohort: the Avon Longitudinal Study of Parents and Children (ALSPAC). We measured emotional symptoms at 7 years with the Strengths and Difficulties Questionnaire. Mothers rated stressful life events between ages 5 and 7 years. Maternal depression was defined as a score ≥12 on the Edinburgh Postnatal Depression Scale at 2 or 8 months postnatally. Triallelic genoptyping of the 5‐HTTLPR polymorphism was performed. We found strong associations between stressful life events (OR 1.19; 1.12–1.26; P < 0.01) and maternal postnatal depression (OR 1.91; 1.63–2.24; P < 0.01) with emotional symptoms in the children. There were no main 5‐HTTLPR genotype effects or significant interactions between genotype and life events or maternal postnatal depression on emotional symptoms. There was marginal evidence (P = 0.08) for an interaction between stressful life events and genotype in boys only, with those in the low and high 5‐HTTLPR expression groups showing stronger associations. In these 7‐year‐old children, we did not replicate previously reported G × E interactions between 5‐HTTLPR and life events for emotional symptoms. Gene by environment interactions may be developmentally dependent and show variation depending on the type and levels of exposure and sex. Young cohorts are essential to improve our understanding of the impact of development on gene and environment interactions.

Additional functional variation at the SLC6A4 gene

), primarily on the role of this polymorphismin susceptibility to major depression and anxiety disorders, and treatment response to SSRIdrugs [Serretti et al., 2006]. Although association to complex behavioral phenotypes has beeninconsistent and meta-analyses reveal modest effects, imaging genetic studies have foundstronger effects of

Zhou et al. reply

Replying to: C. H. Cotton, J. Flint & T. G. Campbell 458, 10.1038/nature07927 (2009)The inability of Cotton et al. to detect an effect of a functional haplotype (and locus) of neuropeptide Y (NPY), a stress regulatory neuropeptide, on neuroticism is interesting. Although it is important to measure effects of functional loci on complex behaviours, the strength of our study, and primary basis of its conclusions, was the larger and convergent effects of NPY on intermediate phenotypes, including regional brain responses to emotional stimuli and pain, and brain NPY messenger RNA and plasma NPY levels. Eysenck Neuroticism is a trait that we did not directly investigate. We reported modest association of NPY with two Harm Avoidance subscales from the Tridimensional Personality Questionnaire. Association of NPY with the complex trait of anxiety, especially when measured differently, is not the first place we would look to validate our results.