Elsevier

Biological Psychiatry

Volume 67, Issue 5, 1 March 2010, Pages 478-486
Biological Psychiatry

Archival Report
Two-Dimensional Genome Scan Identifies Multiple Genetic Interactions in Bipolar Affective Disorder

https://doi.org/10.1016/j.biopsych.2009.10.022Get rights and content

Background

Bipolar disorder is a highly heritable psychiatric condition, the etiology of which remains largely unknown despite extensive efforts to identify susceptibility genes. Interactions between genes of small individual effect could partially explain the difficulties of traditional one-dimensional approaches to identify genetic risk factors.

Methods

A nonparametric linkage (NPL) analysis of 65 Australian extended pedigrees containing 643 genotyped individuals (of whom 40% were diagnosed with affective disorder) was conducted. Chromosome-by-chromosome correlation analysis of family-specific NPL scores was conducted to detect evidence of genetic interaction. Interaction-specific multipoint NPL and permutation analysis was used to assess linkage interdependence, using family weights derived from the alternative interacting chromosome. Finally, a single nucleotide analysis of each interaction region was conducted using the publicly available genome-wide association, datasets (2933 cases, 2534 controls).

Results

Significant NPL peaks were detected on chromosomes 2q24-33, 7q21-31, and 17q11-25 (Z = 3.12, 3.01, and 2.95 respectively), with four additional suggestive peaks identified. Four robust interchromosomal interaction clusters exceeding Bonferroni correction at α = .05 (uncorrected p < 5.38e-07) were detected on 11q23-25–2p15-12, 4q32-35–1p36, 12q23-24–4p16-15, and 20q13–9q21-22. This linkage interdependence was determined significant after permutation analysis (p = .002–.0002). A suggestive interaction was observed in the combined data on 2p14–11q23 (uncorrected p = 5.76E-10, Bonferroni corrected p = .068).

Conclusions

This study indicates a complex interplay between multiple loci underlying bipolar disorder susceptibility, and highlights the continuing usefulness of extended pedigrees in complex genetics. The challenge lies in the identification of specific gene interactions and their biological validation.

Section snippets

Subject Selection and Pedigree Pruning

Pedigrees were ascertained and genotyped using the methods described in Supplement 1. Due to limitations in the linkage analysis program MERLIN (http://www.sph.umich.edu/csg/abecasis/Merlin/index.html) (25), 12 of the 65 pedigrees required trimming of nonessential pedigree members to facilitate a computational analysis of all available families. The reduced cohort consisted of 668 individuals who had completed a Diagnostic Interview for Genetic Studies (DIGS) (26) interview and 643 who had full

Univariate Nonparametric Linkage and Permutation Analysis

Nonparametric linkage analysis for the 373 autosomal and 18 chromosome X microsatellite markers yielded both Z scores and LOD scores that were highly correlated (r = .897). Z scores from single-point linkage analysis using the Sall allele sharing statistic across the genome are shown in Figure 1.

Nominal genome-wide significance was determined via pseudosimulation of 10,000 genome scans that showed that Z scores exceeding 2.8 and 2.5 were to be considered significant (p < .05) and suggestive (p

Discussion

Using a cohort of 65 extended bipolar disorder pedigrees, we have shown evidence for multiple susceptibility loci and a complex pattern of genetic interaction underlying the inheritance of bipolar disorder. Nonparametric linkage in the pooled cohort supports loci detected in five previously reported individual waves of parametric analysis of these families (4q34-35 [20, 24], 13q14 [21, 22], 9q31-33, and 19p13 [22]) and has revealed new loci not previously detected in this cohort under

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