Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study

Lavedan, Christian; Licamele, Louis; Volpi, Simona; Hamilton, Jennifer; Heaton, Callie; Mack, Kendra; Lannan, Rebecca; Thompson, Andrew; Wolfgang, Curt D.; Polymeropoulos, Mihael H.

doi:10.1038/mp.2008.56

Cited by 136 publications

(95 citation statements)

References 56 publications

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“…TNR, which encodes tenascin-R, is an extracellular matrix protein expressed primarily in the central nervous system and has been related to multiple brain diseases. Recent GWASs reported that (1) two SNPs in KIAA0040 (rs1008459 and rs12136973) were significantly associated with amyotrophic lateral sclerosis (Schymick et al, 2007) and two other SNPs in KIAA0040 (rs760486 and rs3766685) were marginally associated with Alzheimer's disease (Li et al, 2008); (2) several SNPs in TNN (rs1009418, rs12065394, rs6672099, rs6681984, and rs16847787) were marginally associated with narcolepsy, a neurological sleep disorder (Miyagawa et al, 2008); and (3) one inter-KIAA0040-TNR SNP (rs875326) was marginally associated with treatment response of schizophrenia to an antipsychotic medication (iloperidone) (Lavedan et al, 2009). These findings support a role for the TNN-KIAA0040-TNR compound locus in the risk for medical disorders, particularly those involving the central nervous system.…”

Section: à5mentioning

confidence: 99%

Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

Zuo

Gelernter

Zhang

et al. 2011

Neuropsychopharmacol

107

128

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Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant geneFKIAA0040Fthat was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of Àlog(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369prp0.824; 2.8 Â 10 À9 ppp0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 Â 10 À11 ppp1.5 Â 10 À6) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.

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Section: à5mentioning

confidence: 99%

Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

Zuo

Gelernter

Zhang

et al. 2011

Neuropsychopharmacol

107

128

View full text Add to dashboard Cite

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“…117 Similarly, SNPs within neuronal PAS domain protein 3 (NPAS3), XK, Kell blood group complex subunit-related family, member 4 (XKR4), tenascin R (TNR), glutamate receptor, ionotropic, AMPA 4 (GRIA4), GFRA2, and the nudix (nucleoside diphosphate linked moiety X)-type motif 9 pseudogene 1 (NUDT9P1) located in the 5-HT receptor 7, adenylate cyclase-coupled (HTR7) gene have been reported to be associated with response to iloperidone. 118 In summary, hypothesis-free GWASs have yielded numerous interesting findings that warrant further investigation.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Pharmacogenetics of Antipsychotics

2014

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Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods:We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses.Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion:First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. W W W La pharmacogénétique des antipsychotiquesObjectif : Au cours des dernières décennies, des efforts croissants ont été déployés dans des études visant à percer l'influence des facteurs génétiques sur le dosage des antipsychotiques (AP), la réponse au traitement, et la survenue d'effets indésirables. Ces études voulaient améliorer les soins cliniques en prédisant le résultat du traitement par AP, et en donnant lieu ainsi à des stratégies de traitement individualisées. Nous présentons les résultats les plus importants obtenus par des études tant de gènes candidats que d'association pangénomique, notamment les facteurs pharmacocinétiques et pharmacodynamiques. Méthodes :Nous avons passé en revue les études sur la pharmacogénétique de la réponse aux AP et des effets indésirables publiées dans PubMed jusqu'au début de 2012. Vu le nombre élevé d'études publiées, notre revue a mis l'accent sur les résultats qui ont été reproduits dans des études indépendantes ou qui sont soutenus par des méta-analyses.

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“…Three common NPAS3 exonic variants have also been recently associated with increased risk of schizophrenia (6). Genetic variation at the NPAS3 locus has also been linked with response to treatment with the antipsychotic drug, iloperidone (7).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

MacIntyre

Machell

et al. 2011

Mol Psychiatry

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The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis-but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients

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Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study

Cited by 136 publications

References 56 publications

Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

Pharmacogenetics of Antipsychotics

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

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