Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

High incidence of late effects found in Hodgkin's lymphoma survivors, following recall for breast cancer screening

Assessment of late effects in a cohort of female Hodgkin's lymphoma patients treated with mantle radiotherapy, identified from the DoH breast cancer screening recall showed high mortality and frequent undiagnosed abnormalities in tissues affected by radiotherapy. With increasing age, this patient group may suffer premature cardiac and respiratory morbidity

Nocturnal Hypoxia and Loss of Kidney Function

Background: Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown. Methods: We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90 % for $12$4 ml/min/1.73 m2 per year. Results: 858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95 % confidence interval [CI] 1.25, 6.67). Conclusion: Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function

Copy number variation in bipolar disorder.

Large (>100 kb), rare (500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4))

Altered DNA methylation associated with a translocation linked to major mental illness

Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions

Body mass index and annual increase of body mass index in long-term childhood cancer survivors; relationship to treatment

Evaluation of body mass index (BMI) at final height (FH) and annual BMI increase in adult childhood cancer survivors (CCS) after treatment with anthracyclines, platinum, and/or radiotherapy. BMI (weight/heightA(2)) was calculated retrospectively from diagnosis until FH. The prevalence of underweight (BMI < 18.5 kg/m(2)) and overweight (BMI a parts per thousand yenaEuro parts per thousand 25 kg/m(2))/obesity (BMI a parts per thousand yenaEuro parts per thousand 30 kg/m(2)) at FH was compared with age-matched controls. The association between underweight/overweight at FH and treatment was assessed by multivariate logistic regression. Annual BMI increase after treatment was assessed by multilevel analysis. Analyses were adjusted for age and underweight/overweight at diagnosis, and age at FH. At FH the prevalence of overweight had not increased, while CCS experienced more underweight as compared to controls (14% vs. 4%, P < 0.001). Overweight at FH was associated with cranial/craniospinal radiotherapy (CRT; OR, 2.23; 95% CI, 1.17-4.26) and underweight at FH with anthracyclines > 300 mg/m(2) (OR, 2.84; 95% CI, 1.33-6.06). Annual BMI increase was +0.47 (0.34-0.60) kg/m(2)/year. In CCS, the annual BMI increase was greater in those with CRT a parts per thousand yenaEuro parts per thousand 30 Gy as compared with those with less or no CRT (+0.15 kg/m(2)/year [0.04-0.25 kg/m(2)/year], P = 0.008) and smaller in those with a higher cumulative anthracycline dose (-0.03 kg/m(2)/year [-0.05 to -0.0005 kg/m(2)/year] per 100 mg/m(2), P = 0.046). After treatment with anthracyclines, platinum, and/or radiotherapy, CRT-treated survivors have more overweight at FH, and a greater annual BMI increase, while anthracycline-treated survivors have more underweight at FH and a lower annual BMI increase

Genome-Wide Association Study in Bipolar Patients Stratified by Co-Morbidity

Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia