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Bipolar disorder is a highly heritable polygenic disorder. Recent
enrichment analyses suggest that there may be true risk variants for
bipolar disorder in the expression quantitative trait loci (eQTL) in the
We sought to assess the impact of eQTL variants on bipolar disorder risk
by combining data from both bipolar disorder genome-wide association
studies (GWAS) and brain eQTL.
To detect single nucleotide polymorphisms (SNPs) that influence
expression levels of genes associated with bipolar disorder, we jointly
analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls)
and a genome-wide brain (cortical) eQTL (193 healthy controls) using a
Bayesian statistical method, with independent follow-up replications. The
identified risk SNP was then further tested for association with
hippocampal volume (n = 5775) and cognitive performance
(n = 342) among healthy individuals.
Integrative analysis revealed a significant association between a brain
eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes
factor = 5.48; bipolar disorder P =
5.85×10–5). Follow-up studies across multiple independent
samples confirmed the association of the risk SNP (rs6088662) with gene
expression and bipolar disorder susceptibility (P =
3.54×10–8). Further exploratory analysis revealed that
rs6088662 is also associated with hippocampal volume and cognitive
performance in healthy individuals.
Our findings suggest that 20q11.22 is likely a risk region for bipolar
disorder; they also highlight the informative value of integrating
functional annotation of genetic variants for gene expression in
advancing our understanding of the biological basis underlying complex
disorders, such as bipolar disorder.
The study focused on: (1) the existence of genetic anticipation in a randomly selected sample of bipolar I patients using broad and narrow definitions of the affection status in the parental generation; (2) the relationship between anticipation and the age at investigation in probands and in their relatives; (3) the relationship between anticipation and imprinting.
One hundred and fifteen bipolar I patients and their first- to third-degree relatives were diagnosed according to DSM–III–R criteria using the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies.
Age at onset was found to be 6–10 years younger in probands with affected parents or uncles/aunts. Two-thirds of these families showed positive anticipation under both the broad and the narrow definitions of affection status in the parents' generation. The age at investigation was younger in probands showing positive anticipation. Anticipation was found only in probands inheriting the disorder from the paternal side.
In spite of the inevitable association between young current age and young age at onset, which could result in spurious anticipation effects, our findings suggest that this phenomenon is not the sole cause of observed anticipation.
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