Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Association between variation in the vesicular monoamine transporter 1 gene on chromosome 8p and anxiety-related personality traits

Vesicular monoamine transporters are involved in the presynaptic packaging of norepinephrine, dopamine and serotonin into storage vesicles. The vesicles release their content upon arrival of an action potential into the synaptic cleft. Dysregulation of monoaminergic neurotransmission has been long postulated to play a relevant role in the etiology of neuropsychiatric disorders. The gene encoding the vesicular monoamine transporter 1 (VMAT1/SLC18A1) maps to chromosome 8p21, a region where several linkage peaks overlap between schizophrenia, bipolar disorder and anxiety-related personality traits. In this study, we tested the hypothesis that the missence variation Thr136Ile in the VMAT1/SLC18A1 gene is associated with anxiety-related personality traits. We tested a total of 337 unrelated subjects of German descent (167 male, 170 female). All participants were carefully screened for psychiatric disorders. The self-report State-Trait Anxiety Inventory (STAI) was completed by all subjects. Genotypes were obtained for the Thr136Ile (rs1390938) variation in the VMAT1 gene for all subjects. Genotype effects on personality variables were computed with MANOVA including age as a co-variant and gender as independent factor (MANCOVA). Results show that STAI scores were significantly affected by genotype (F=3.108; d.f.=4,331; p=0.015) and age (F=7.233; d.f.=2,331; p=0.001) but not by gender. A gender-by-genotype effect was observed for both the STAI state (p=0.052) and trait score (p=0.035). Dissection of the group by gender and subsequent contrast analysis of the genotype effects performed within the female group showed significant results (STAI state: Thr/Ile vs. Ile/Ile: T=4.408, p=0.0004; STAI trait: Thr/Ile vs. Ile/Ile: T=3.074, p=0.009) but not in the male group. Our findings support the hypothesis that anxiety-related personality traits are associated with variation in the VMAT1/SLC18A1 gene

Variations in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) are associated with bipolar I disorder

The vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) maps to the shared bipolar disorder (BPD)/schizophrenia (SZ) susceptibility locus on chromosome 8p21. Vesicular monoamine transporters are involved in transport of monoamine neurotransmitters which have been postulated to play a relevant role in the etiology of BPD and/or SZ. Variations in the VMAT1 gene might affect transporter function and/or expression and might be involved in the etiology of BPD and/or SZ. Genotypes of 585 patients with BPD type I and 563 control subjects were obtained for three missense single nucleotide polymorphisms (SNPs) (Thr4Pro, Thr98Ser, Thr136Ile) and four non-coding SNPs (rs988713, rs2279709, rs3735835, rs1497020). All cases and controls were of European descent. Allele frequencies differed significantly for the potential functional polymorphism Thr136Ser between BPD patients and controls (p=0.003; df=1; OR=1.34; 95% CI: 1.11-1.62). Polymorphisms in the promoter region (rs988713: p=0.005, df=1; OR=1.31; 95% CI: 1.09-1.59) and intron 8 (rs2279709: p=0.039, df=1; OR=0.84; 95% CI: 0.71-0.99) were also associated with disease. Expression analysis confirmed that VMAT1 is expressed in human brain at the mRNA and protein level. Results suggest that variations in the VMAT1 gene may confer susceptibility to BPD in patients of European descent. Additional studies are necessary to confirm this effect and to elucidate the role of VMAT1 in central nervous system physiology

Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility

Purpose: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. Methods: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing™ were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n=407) and unrelated controls (n=284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n=153), childhood absence (n=84), juvenile myoclonic (n=111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n=59) and all were of European ancestry. Results: SNP rs#1130183 (C>T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square=5.65, d.f.=1, P=0.017, odds ratio 0.52, 95% CI 0.33-0.82. Conclusion: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans

A linkage study of bipolar illness

BACKGROUND: Although genetic epidemiological studies of bipolar (BP) illness are consistent with a heritable component, inherited risk factors remain unknown. The goal of the present study is to describe the localization of BP susceptibility loci through linkage strategies, including a genome-wide search. METHODS: A linkage study of 22 BP families has been performed. These BP families include almost 400 persons, 173 of whom have been diagnosed as having BP I, schizoaffective, BP II with major depression, or recurrent unipolar illness. Using an autosomal dominant disease model with 85% or 50% age-dependent penetrance, and a recessive model with 85% penetrance, linkage analyses were performed assuming a narrow (BP and schizoaffective) or a broad (BP, schizoaffective, or unipolar) definition of the BP spectrum. Affected sibling pairs and affected pedigree member analyses were performed when positive lod scores were observed in multiple pedigrees. The present article describes linkage analysis of 310 DNA markers on chromosomes 1, 5p, 6, 8, 10q, 11q, and 12 to 18. RESULTS: None of the loci examined disclosed compelling evidence for linkage using lod score analyses. Model-independent analysis by multilocus affected pedigree member method in the pericentromeric chromosome 18 region disclosed statistically significant evidence (P < .0001) for a BP susceptibility gene in this region. Multilocus analysis by affected sibling pair method also disclosed evidence for linkage (P < .00008). CONCLUSIONS: Our results imply that a BP susceptibility gene exists near the centromere of chromosome 18. Confirmation of this finding (by independent investigators studying different pedigrees) has been published, suggesting that a valid BP disease linkage may have been discovered