Malfunctioning circadian clock genes may be responsible for bipolar disorder in children. Researchers writing in the open access journal BMC Psychiatry found four versions of the regulatory gene RORB that were associated with pediatric bipolar disorder.

Alexander Niculescu from Indiana University School of Medicine, Indianapolis, US, worked with a team of researchers at Harvard, UC San Diego, Massachusetts General Hospital and SUNY Upstate Medical University to study the RORA and RORB genes of 152 children with the condition and 140 control children. They found four alterations to the RORB gene that were positively associated with being bipolar. Niculescu said, “Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder”.

RORB is mainly expressed in the eye, pineal gland and brain. Its expression is known to change as a function of circadian rhythm in some tissues, and mice without the gene exhibit circadian rhythm abnormalities. According to Niculescu, “Bipolar disorder is often characterized by circadian rhythm abnormalities, and this is particularly true among pediatric bipolar patients. Decreased sleep has even been noted as one of the earliest symptoms discriminating children with bipolar disorder from those with attention deficit hyperactivity disorder (ADHD). It will be necessary to verify our association results in other independent samples, and to continue to study the relationship between RORB, other clock genes, and bipolar disorder”.

Pediatric bipolar disorder is a controversial diagnosis characterized by alternating bouts of depression and mania in children, although it does not affect all young people in the same way and the duration and severity of the disorder can vary enormously.

Notes:

Evidence for Genetic Association of RORB with Bipolar Disorder
Casey L McGrath, Stephen J Glatt, Pamela Sklar, Helen Le-Niculescu, Ronald Kuczenski, Alysa E Doyle, Joseph Biederman, Eric Mick, Stephen V Faraone, Alexander B Niculescu and Ming T Tsuang
BMC Psychiatry (in press)

http://www.biomedcentral.com/bmcpsychiatry/

Source: Graeme Baldwin

BioMed Central

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Several single nucleotide polymorphisms (SNPs) are linked to response to lithium for the prevention of recurrence in bipolar disorder, including in a region spanning a gene regulated by lithium, say scientists.

As many as 50% of bipolar disorder patients experience recurrence within a year of resolution of an acute episode. While lithium is a first-line treatment for bipolar disorder, it is not clear by which mechanisms the drug prevents the recurrence of mood episodes.

To determine associations between lithium treatment outcomes and SNPs, Roy Perlis, from Massachusetts General Hospital in Boston, and colleagues genotyped 1177 patients with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD). Of these, 458 were being treated with lithium carbonate or citrate.

The team then took the SNPs with the greatest evidence of association with lithium responses and examined them for association with positive lithium response among 359 bipolar I or II disorder patients in a cohort from University College London, all of whom were treated with lithium.

The genome-wide analysis of the STEP-BD cohort included approximately 1.4 million SNPs. No SNPs met the threshold for genome-wide significance. However, the greatest evidence of association was seen for an SNP on chromosome 10p15, with three other regions on 21q21, 12q22, and 6p21 found to have significant associations, while others had evidence suggestive of association.

Analysis of the University College London cohort revealed that nine SNPs were associated with lithium responses, five of which, on regions 8q22, 3p22, 11q14, 4q32, and 15q26, had the same direction of effect as seen in the STEP-BD cohort. Logistic regression analysis indicated that SNPs in the five regions were associated with lithium response at hazard ratios of 1.62, 1.45, 1.37, 1.40, 1.47, respectively, in the STEP-BD cohort and odds ratios of 1.71, 1.63, 1.60, 1.48, and 1.81, respectively, in the University College London cohort.

The team observes in the American Journal of Psychiatry that the region 4q32 spans the gene encoding the subunit of the ligand-gated ionotrophic glutamate receptor GluR2/GLURB, which binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate and is downregulated by chronic lithium treatment.

“Taken together, our results do suggest a number of regions meriting further investigation,” the team says. “They further highlight the importance of collecting adequate replication cohorts with detailed longitudinal outcomes if the effect of genetic variation on lithium response is to be understood.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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