Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm

T. Bernard Bigdeli, Brion Maher, Zhongming Zhao, Jingchun Sun, Helena Medeiros, Nirmala Akula, Francis J. Mcmahon, Celia Carvalho, Susana R. Ferreira, Maria H. Azevedo, James A. Knowles, Michele T. Pato, Carlos N. Pato, Ayman H. Fanous

Research output: Contribution to journalArticle

Abstract

Background: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. Methods: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N=1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. Results: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. Conclusions: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Published 2013.

Original languageEnglish (US)
Pages (from-to)898-906
Number of pages9
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume162
Issue number8
DOIs
StatePublished - Dec 2013

Fingerprint

Genetic Association Studies
Bipolar Disorder
Chromosomes
Genes
Linkage Disequilibrium
National Institute of Mental Health (U.S.)
Single Nucleotide Polymorphism
Islands
Public Sector
Chromosome Mapping
Pedigree
Genome

Keywords

  • 6q
  • Bipolar disorder
  • Gene-based association
  • Genetic association

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm. / Bigdeli, T. Bernard; Maher, Brion; Zhao, Zhongming; Sun, Jingchun; Medeiros, Helena; Akula, Nirmala; Mcmahon, Francis J.; Carvalho, Celia; Ferreira, Susana R.; Azevedo, Maria H.; Knowles, James A.; Pato, Michele T.; Pato, Carlos N.; Fanous, Ayman H.

In: American Journal of Medical Genetics - Neuropsychiatric Genetics, Vol. 162, No. 8, 12.2013, p. 898-906.

Research output: Contribution to journalArticle

Bigdeli, TB, Maher, B, Zhao, Z, Sun, J, Medeiros, H, Akula, N, Mcmahon, FJ, Carvalho, C, Ferreira, SR, Azevedo, MH, Knowles, JA, Pato, MT, Pato, CN & Fanous, AH 2013, 'Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm', American Journal of Medical Genetics - Neuropsychiatric Genetics, vol. 162, no. 8, pp. 898-906. https://doi.org/10.1002/ajmg.b.32200
Bigdeli, T. Bernard ; Maher, Brion ; Zhao, Zhongming ; Sun, Jingchun ; Medeiros, Helena ; Akula, Nirmala ; Mcmahon, Francis J. ; Carvalho, Celia ; Ferreira, Susana R. ; Azevedo, Maria H. ; Knowles, James A. ; Pato, Michele T. ; Pato, Carlos N. ; Fanous, Ayman H. / Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm. In: American Journal of Medical Genetics - Neuropsychiatric Genetics. 2013 ; Vol. 162, No. 8. pp. 898-906.
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AU - Bigdeli, T. Bernard

AU - Maher, Brion

AU - Zhao, Zhongming

AU - Sun, Jingchun

AU - Medeiros, Helena

AU - Akula, Nirmala

AU - Mcmahon, Francis J.

AU - Carvalho, Celia

AU - Ferreira, Susana R.

AU - Azevedo, Maria H.

AU - Knowles, James A.

AU - Pato, Michele T.

AU - Pato, Carlos N.

AU - Fanous, Ayman H.

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N2 - Background: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. Methods: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N=1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. Results: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. Conclusions: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Published 2013.

AB - Background: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. Methods: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N=1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. Results: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. Conclusions: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Published 2013.

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