Searching Susceptibility Loci for Bipolar Disorder: A Sib Pair Study on Chromosome 12

Abstract

Background/Aims: Several linkage studies demonstrated that different chromosomal regions are involved in the susceptibility to bipolar disorder. In particular, some genome scans evidenced the role of chromosome 12. For this reason, our group chose this chromosome for a preliminary genome scan on a sample of 137 Italian sib pairs, including at least 1 bipolar subject. Methods: The analyses were carried out by means of DNA extracted from whole blood. DNA samples were genotyped by 19 simple tandem repeat markers (microsatellites). Starting from the genetic data, we performed two- and multipoint linkage analyses (both parametric and nonparametric) by means of Easy Linkage plus package (version 5.05). Results: The multipoint linkage analyses pointed out a region suggestive of linkage between the markers D12S310 and D12S364, at locus 12p12. In particular, we reached the best evidence of linkage performing multipoint analyses and assuming a recessive model, under the hypothesis of genetic heterogeneity (heterogeneity LOD score = 2.01 and α = 0.77). Conclusion: It is interesting to notice that the region at the marker D12S364 is located inside the gene coding for the glutamatergic receptor GRIN2B. Therefore, our finding not only confirmed the role of genetics in determining liability to bipolar disorder, but suggested glutamatergic transmission impairment as a possible cause. Nevertheless, we acknowledge that our study is heavily underpowered. Therefore, independent replication is needed.

Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

“…Although it did not reach the genome-wide significant threshold, the most associated region in our meta-analysis was located on chromosome 12p12. This region has been previously associated with bipolar disorder [40]–[42] and more specifically when patients had an early age at onset of mania [40]. Five SNPs in this region showed a difference in allele frequencies between patients and controls, spanning two genes, PLEKHA5 and AEBP2 .…”

Expression profiling in neuropsychiatric disorders: Emphasis on glutamate receptors in bipolar disorder

“…Specific glutamatergic neurotransmission candidate susceptibility genes include citron (CIT) positive (Lyons-Warren et al, 2005) and negative (Yosifova et al, 2009), D-amino acid oxidase (DAO) positive (Fallin et al, 2005; Prata et al, 2008) and negative (Shi et al, 2008), and the nitric oxide synthase (NOS) genes NOS1 (neuronal) positive (Fallin et al, 2005; Yosifova et al, 2009) and negative (Buttenschon et al, 2004; Gratacos et al, 2009; Okumura et al, 2010), and NOS3 (endothelial) positive (Reif et al, 2006) and negative (Gratacos et al, 2009; Sklar et al, 2002). GluRs identified as BP candidate genes include the ionotropic α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor subunits GRIA1 positive (Kerner et al, 2009; Shi et al, 2008) and negative (Gratacos et al, 2009), GRIA2 positive (Perlis et al, 2009) and negative (Shi et al, 2008; Sklar et al, 2002), kainate (KA) receptor subunit GRIK4 positive (Pickard et al, 2008; Pickard et al, 2006) and negative (Gratacos et al, 2009), N-methyl-D-aspartate (NMDA) receptor subunits GRIN1 positive (Mundo et al, 2003; Shi et al, 2008; Yosifova et al, 2009) and negative (Georgi et al, 2006), GRIN2A positive (Itokawa et al, 2003) and negative (Gratacos et al, 2009; Shi et al, 2008), GRIN2B positive (Avramopoulos et al, 2007; Fallin et al, 2005; Lorenzi et al, 2010; Martucci et al, 2006; Zhao et al, 2011) and negative (Gratacos et al, 2009; Shi et al, 2008), GRIN2C positive (Shi et al, 2008), and GRIN2D positive (Shi et al, 2008), and metabotropic glutamate receptors (mGluRs) GRM1 positive (Baum et al, 2008; Frank et al, 2011) and negative (Fan et al, 2010; Shi et al, 2008), GRM3 positive (Fallin et al, 2005; Sklar et al, 2008) and negative (Gratacos et al, 2009; Marti et al, 2002; Shi et al, 2008; Yosifova et al, 2009), GRM4 positive (Fallin et al, 2005) and negative (Shi et al, 2008; Sklar et al, 2002), GRM7 positive (Gratacos et al, 2009) and negative (Baum et al, 2008; Shi et al, 2008; Sklar et al, 2002; Yosifov...…”

GRIN2B Gene and Associated Brain Cortical White Matter Changes in Bipolar Disorder: A Preliminary Combined Platform Investigation

“…Encoded by the GRIN2B gene, which is located at 12p12 and 419 kb in size, this subunit is expressed in the cortical and medial temporal parts of the brain, striatum, and olfactory bulb [7, 8]. Earlier studies have explored the relationship between GRIN2B gene and BD [9–12]. A genetic study of Italian patients with BD found linkage to marker D12S364 at locus 12p12 within the GRIN2B gene [9].…”

“…Earlier studies have explored the relationship between GRIN2B gene and BD [9–12]. A genetic study of Italian patients with BD found linkage to marker D12S364 at locus 12p12 within the GRIN2B gene [9]. Another study of 440 single-nucleotide polymorphisms (SNPs) from 64 candidate genes among Ashkenazi Jewish case-parent trios with bipolar I disorder noted the aforementioned association of GRIN2B with BD [10], and this was confirmed by a follow up study [11].…”