A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT<sub>1A</sub>Receptor Binding in Humans

David, Sean P.; Murthy, Naga Venkatesha; Rabiner, Eugenii A.; Munafò, Marcus R.; Johnstone, Elaine; Jacob, Robyn; Walton, Robert; Grasby, Paul M.

doi:10.1523/jneurosci.3769-04.2005

Cited by 240 publications

(207 citation statements)

References 32 publications

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“…62,63 There are indications that a known functional polymorphism (5-HTTLPR) may affect the expression of the functionally related but distinct 5-HT1A receptors, offering a plausible pathophysiological mechanism for several mood disorders and behavioral traits. 64 However, studies probing associations of 5-HTTLPR with autism reached conflicting results. [65][66][67][68] The serotonin system is quite diffuse, affecting many different physiological mechanisms, and it may be difficult to assume a pathophysiological pathway specific for autism-spectrum disorders.…”

Section: Discussionmentioning

confidence: 99%

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

et al. 2005

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Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.

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Section: Discussionmentioning

confidence: 99%

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

et al. 2005

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“…83,84 Lower availability of the 5-HT1A receptor in 5-HTTLPR s allele carriers has been reported and awaits replication. 85 While single measurements of 5-HTT availability and serotonin turnover have not provided a consistent picture, specific challenge tests may be better suited to reveal differences in central nervous reactivity associated with 5-HTTLPR. For example, most neuroendocrine tests of central serotonergic function have shown blunted responses in s allele carriers; these include smaller prolactin increases in response to fenfluramine, clomipramine or citalopram.…”

Section: The Functionality Of 5-httlprmentioning

confidence: 99%

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

2007

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“…While this in vitro effect was initially confirmed using in vivo single photon emission computed tomography (SPECT) [25], recent PET studies offering more specific radiotracers and improved spatial resolution have failed to find altered 5-HTT levels associated with the 5-HTTLPR [26,27]. Rather, effects of the 5-HTTLPR have been documented in other 5-HT subsystems, most notably the 5-HT 1A receptor [28,29], and such downstream effects may be critical in mediating the neural and behavioral effects of the 5-HTTLPR [30,31].…”

Section: ) Common Polymorphisms Impacting the Amygdala And Temperamementioning

confidence: 99%

Neuroimaging: Technologies at the Interface of Genes, Brain, and Behavior

Bigos

Hariri

2007

Neuroimaging Clinics of North America

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SynopsisNeuroimaging technologies, because of their unique ability to capture the structural and functional integrity of distributed neural circuitries within individuals, provide a powerful approach to explore the genetic basis of individual differences in complex behaviors and vulnerability to neuropsychiatric illness. Functional magnetic resonance imaging (MRI) studies especially have established important physiological links between genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and depression. Importantly, many of these biological relationships have been revealed in relatively small samples of subjects and in the absence of observable differences at the level of behavior, underscoring the power of a direct assay of brain anatomy and physiology in exploring the functional impact of genetic variation. Through the continued integration of genes, brain and behavior, neuroimaging technologies represent a critical tool in ongoing efforts to understand the neurobiology of normal and pathological behavioral states. Multidisciplinary research capitalizing on such neuroimaging-based integration will contribute to the identification of predictive markers and biological pathways for neuropsychiatric disease vulnerability as well as the generation of novel targets for therapeutic intervention. CONCEPTUAL BASIS AND OVERVIEWGenes have unparalleled potential impact on all levels of biology. In the context of disease states, particularly behavioral disorders, genes represent the cornerstone of mechanisms that, either directly or in concert with environmental events, ultimately result in disease. Moreover, genes offer the potential to identify at-risk individuals and biological pathways for the development of new treatments. While most human behaviors cannot be explained by genes alone, and certainly much variance in aspects of brain structure and function will not be genetically determined directly, it is anticipated that variations in genetic sequence impacting function will contribute an appreciable amount of variance to these resultant complex biological and behavioral phenomena. This conclusion is implicit in the results of studies of twins that have revealed heritabilities ranging from 40 to 70% for various aspects of cognition, temperament, and personality [1]. In the case of psychiatric illness, genes appear to be the only consistent risk factors that have been identified across populations, and the majority of susceptibility for major psychiatric disorders is accounted for by inheritance [2].

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A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT_1AReceptor Binding in Humans

Cited by 240 publications

References 32 publications

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

Neuroimaging: Technologies at the Interface of Genes, Brain, and Behavior

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A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1AReceptor Binding in Humans

Cited by 240 publications

References 32 publications

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

Neuroimaging: Technologies at the Interface of Genes, Brain, and Behavior

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Product

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A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT_1AReceptor Binding in Humans