Family-based association of an ANK3 haplotype with bipolar disorder in Latino populations

Gonzalez, Suzanne; Chun, Xu; Ramirez, Mercedes; Zavala, Juan; Armas, Regina; Contreras, Salvador; Contreras, Javier; Dassori, Albana M; Leach, Robin J.; Flores, Deborah; Jerez, Alvaro; Raventós, Henriette; Ontiveros, Alfonso; Nicolini, Humberto; Escamilla, Michael

doi:10.1038/tp.2013.40

Cited by 6 publications

(4 citation statements)

References 10 publications

(10 reference statements)

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“…In contrast, the SNPs rs100994336 and rs9804190 in ANK3 were not significantly associated with Pakistani BD (Table 2). This result suggests that SNPs associated with BD may vary based on ethnic background as has been shown in previous studies, or it may be in part due to the smaller sample size utilized in this study (Takata et al, 2011; Gonzalez et al, 2013).…”

Section: Discussionmentioning

confidence: 53%

Association of CACNA1C with bipolar disorder among the Pakistani population

Khalid

Driessen

Lee

et al. 2018

Gene

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Many single nucleotide polymorphisms (SNPs) have been identified for Bipolar disorder (BD), but association between SNPs and BD can vary depending on the population tested. SNPs rs10994336 and rs9804190 in ANK3 and rs1006737 in CACNA1C have emerged as the most highly replicated SNPs significantly associated with BD. The aim of the present study was to assess the association of these SNPs with BD in the Pakistani population, which has never before been examined. A total of 120 BD and 120 control individuals from Pakistan were examined in this analysis. Genotyping results indicated that rs1006737 in CACNA1C was significantly associated with BD, while rs10994336 or rs9804190 in ANK3 was not significant when examined individually. However, risk score assessment found that the presence of two or more risk alleles was significantly associated with disease, indicating that risk alleles from ANK3 and CACNA1C may additively contribute to BD. A protein-protein interaction network was generated using STRING to probe the relationship between ANK3 and CACNA1C interactors and their associations with BD. While none of the interactors are directly linked to BD, they play a role in pathways linked to BD, including oxytocin and dopamine signaling pathways. Collectively, these results reveal a significant association of CACNA1C with BD among the Pakistani population, extending results from other ethnic groups to the Pakistani population for the first time.

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Section: Discussionmentioning

confidence: 53%

Association of CACNA1C with bipolar disorder among the Pakistani population

Khalid

Driessen

Lee

et al. 2018

Gene

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“…We previously reported haplotype associations with BD in two genes (calcium voltage‐gated channel subunit alpha1 C [ CACNA1C ] and ankyrin 3 [ ANK3 ] involved in calcium signaling, previously found to be associated with psychiatric disease in European populations . We reported a positive association between an eight‐locus haplotype in CACNA1C and BD (permuted P =.005; global marker permuted P =.002) and between a six‐locus haplotype block in ANK3 and BD (permuted P =.025; global marker permuted P =.021) . The current study was designed to expand on these previous findings by testing additional markers identified through GWASs of both BD and SC in a larger Latino sample.…”

Section: Discussionmentioning

confidence: 94%

“…15 We reported a positive association between an eight-locus haplotype in CACNA1C and BD (permuted P=.005; global marker permuted P=.002) 53 and between a sixlocus haplotype block in ANK3 and BD (permuted P=.025; global marker permuted P=.021). 54 The current study was designed to expand on these previous findings by testing additional markers identified through GWASs of both BD and SC in a larger Latino sample. To the best of our knowledge, this is the largest study to date to replicate BD/SC GWAS findings from primarily European and Asian populations in Latino BD cohorts.…”

Section: Discussionmentioning

confidence: 99%

Replication of genome‐wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort

et al. 2016

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Objectives: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. Methods:A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations.Results: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5′-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. Conclusions:These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos.Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD. K E Y W O R D Sbipolar disorder, Central American, family studies, genetics, lysosomal associated membrane protein 3 (LAMP3), Latinos, Mexican, Mexican-American, nuclear factor kappa B subunit 1 (NFKB1), serologically defined colon cancer antigen 8 (SDCCAG8)

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“…However, the existing data on ANK3 show that only low-frequency aetiological base-pair (bp) changes are present with an odds ratio less than 1.35 for BP 17 . The SNP associations are not replicated in every study 36 – 39 ; however, the ANK3 association has been reported in several different ancestral populations 36 , 40 – 42 . Several novel, rare potential aetiological bp changes have been identified by us through sequencing the gene in our samples.…”

mentioning

confidence: 89%

Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data

Fiorentino

O’Brien

Locke³

et al. 2014

Bipolar Disorders

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ObjectivesGenetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.MethodsIn order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.ResultsWe found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.ConclusionsSequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called ‘missing heritability’ of BP.

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Family-based association of an ANK3 haplotype with bipolar disorder in Latino populations

Cited by 6 publications

References 10 publications

Association of CACNA1C with bipolar disorder among the Pakistani population

Association of CACNA1C with bipolar disorder among the Pakistani population

Replication of genome‐wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort

Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data

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