Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 À141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 À141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.

Background Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. Methods Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. Results Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. Conclusions Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.

Background 5-HT1A autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating 5-HT signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C(-1019)G) in the human 5-HT1A gene (HTR1A) represents one potential source of such inter-individual variability. Both in vitro and in vivo the -1019G blocks transcriptional repression leading to increased autoreceptor expression. Thus, the -1019G may contribute to relatively decreased 5-HT signaling at postsynaptic forebrain target sites via increased negative feedback. Objectives & Design To use imaging genetics to evaluate the effects of HTR1A C(-1019)G on amygdala reactivity in 89 healthy adults and employ path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that the -1019G, which potentially results in decreased 5-HT signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. Results Consistent with prior findings, the -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism impacting 5-HT signaling, namely the 5-HTTLPR. While there were no direct genotype effects on trait anxiety, the HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. Conclusions Our findings further implicate relatively increased 5-HT signaling, associated with genetic variation mediating increased 5-HT1A autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation impacts emergent behavioral processes related to psychiatric disease risk indirectly by biasing the response of underlying neural circuitries.