Carriers of the short allele of a functional 5' promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.

A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (G×E) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for G×E research. The authors discuss how G×E interaction hypotheses can be tested with large and small samples, how G×E research can be carried out before as well as after replicated gene discovery, the uses of G×E research as a tool for gene discovery, the importance of construct validation in evaluating G×E research, and the contribution of G×E research to the public understanding of genetic science.

BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.

Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val 158 -met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val͞val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met͞met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-''U'' functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met͞met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine. A mphetamine (AMP) and other psychostimulants are among the most effective psychotropic medications in clinical use and the mainstay of treatment for patients with attention deficit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue syndrome, and apathy and anhedonia of diverse etiologies. There is general consensus that these drugs increase CNS alertness, modulate attention, and enhance mood and cognitive performance by potentiating monaminergic neurotransmission. Because of these effects, and the reinforcing properties of monoaminergic stimulation, AMP and related compounds are popular substances of abuse. Although it has been well known that there are dose-and behavior-dependent differential effects of psychostimulants (1, 2), there is also considerable evidence that the response to these drugs varies across individuals, even to fixed doses (3-5). These variable effects have been difficult to predict a priori and to date no neurobiological explanation for them has been established. It is possible that some of the intersubject differences can be explained by functional polymorphisms in monoamine system genes (e.g., synaptic proteins, metabolic enzymes, etc.) that effect baseline monoaminergic tone.While AMP blocks the action of transporters at dopaminergic, serotonergic, and noradrenergic neurons, its positive effects on attention and cognition appear to be mediated principally at the prefrontal cor...

The patterns of comorbidity among prevalent mental disorders in adults lead them to load on ‘externalizing,’ ‘distress,’ and ‘fears’ factors. These factors are themselves robustly correlated, but little attention has been paid to this fact. As a first step in studying the implications of these inter-factor correlations, confirmatory factor analyses were conducted on diagnoses of 11 prevalent DSM-IV mental disorders in a nationally representative sample. A model specifying correlated externalizing, distress, and fears factors fit well, but an alternative model was tested in which a ‘general’ bifactor was added to capture what these disorders share in common. There was a modest but significant improvement in fit for the bifactor model relative to the 3-factor oblique model, with all disorders loading strongly on the bifactor. Tests of external validity revealed that the fears, distress, and externalizing factors were differentially associated with measures of functioning and potential risk factors. Nonetheless, the general bifactor accounted for significant independent variance in future psychopathology, functioning, and other criteria over and above the fears, distress, and externalizing factors. These findings support the hypothesis that these prevalent forms of psychopathology have both important common and unique features. Future studies should determine if this is because they share elements of their etiology and neurobiological mechanisms. If so, the existence of common features across diverse forms of prevalent psychopathology could have important implications for understanding the nature, etiology, and outcomes of psychopathology.

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