Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study

Kuo, Po-Hsiu; Chuang, Li-Chung; Liu, Je-Ruei; Liu, C.M.; Huang, Ming; Lin, Shih‐Ku; Sun, Han; Hsieh, Ming H.; Hung, Hung; Lu, Ru‐Band

doi:10.1016/j.pnpbp.2014.01.003

Cited by 27 publications

(21 citation statements)

References 51 publications

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“…Results of studies based on candidate gene approach and investigating genetic variation within the Hcy metabolism enzymes should be interpreted with caution. Previous genome-wide association studies (GWAS) have not confirmed the association between polymorphisms in the MTHFR gene or other genes implicated in Hcy metabolism and schizophrenia (Yoshimi et al, 2010 ; Lencz et al, 2013 ; Ripke et al, 2013 , 2014 ; Ivorra et al, 2014 ; Saito et al, 2014 ) or bipolar disorder (Sklar et al, 2011 ; Kuo et al, 2014 ; Mühleisen et al, 2014 ; Xu et al, 2014 ) risk. There is only one genome-wide linkage analysis of recurrent depressive disorder providing evidence for linkage on chromosome region 1p36 including the MTHFR gene with the LOD score for female-female pairs estimated at 2.73 (McGuffin et al, 2005 ).…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Homocysteine levels in schizophrenia and affective disordersâ€”focus on cognition

Moustafa

Hewedi

Eissa

et al. 2014

Front. Behav. Neurosci.

120

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Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.

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Section: Future Directions and Conclusionmentioning

confidence: 99%

Homocysteine levels in schizophrenia and affective disordersâ€”focus on cognition

Moustafa

Hewedi

Eissa

et al. 2014

Front. Behav. Neurosci.

120

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“…Voltage-gated ion channels have previously been implicated in a number of psychiatric disorders, including bipolar disorder, due to their known involvement in neuronal excitability and synaptic transmission [71]. Association at the KCNH7 locus with bipolar disorder was also reported at rs6736615, an intronic variant, in a recent case-control study of 400 Taiwanese subjects [72]. Moreover, an exome-sequencing study of a small number of Amish subjects with mental illness identified rs78247304 as a likely risk variant and showed that the Arg394His substitution leads to altered voltage dependence and activation kinetics of the channel in patch clamp experiments [73].…”

Section: Discussionmentioning

confidence: 93%

Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

et al. 2014

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Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

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“…There are several lines of evidence supporting the potential relevance of the finding. Potassium channels have been linked to psychiatric illnesses such as bipolar disorder, schizophrenia and autism (Askland et al 2009;Belengeanu et al 2014;Gargus 2006;Griswold et al 2015;Heide et al 2012;Imbrici et al 2013;Kuo et al 2014;Strauss et al 2014). One potassium channel gene, KCNH2, which is well known as a cause of long QT syndrome (Curran et al 1995) and antipsychotic-related prolonged QT interval (Kongsamut et al 2002), was found to be associated with processing speed and schizophrenia (Atalar et al 2010;Huffaker et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Bruce

Kochunov

Paciga

et al. 2017

Genes Brain and Behavior

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Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder, and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes- processing speed, whole-brain white matter fractional anisotropy, and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased fractional anisotropy, and increased risk of schizophrenia spectrum disorder. A single SNP, rs8234, in the 3′ untranslated region (UTR) of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity, and increased risk of schizophrenia.

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Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study

Cited by 27 publications

References 51 publications

Homocysteine levels in schizophrenia and affective disordersâ€”focus on cognition

Homocysteine levels in schizophrenia and affective disordersâ€”focus on cognition

Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

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