BackgroundLithium remains a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers have been reproducibly identified.MethodsHere we report the results of a genome-wide association study of lithium response in 2,563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen); the largest attempted so far. Data from over 6 million common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response of known reliability.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003: p=1·37×10−8; rs78015114: p=1·31×10−8; rs74795342: p=3·31×10−9; rs75222709: p=3·50×10−9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to two years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03, hazard ratio = 3·8).InterpretationThe response-associated region contains two genes coding for long non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Further studies are needed to establish the biological context of these findings and their potential clinical utility. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder.

Background The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer’s disease (AD). The aims of the present study were to: 1) examine the cross-sectional relationship between fornix DTI measurements (fractional anisotropy (FA), and mean (MD), axial (DA) and radial (DR) diffusivities), hippocampal volume, and memory performance, and 2) compare fornix DTI measures to hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment (MCI) to AD dementia. Methods 23 MCI participants with baseline hippocampal volumetry and diffusion tensor imaging received detailed evaluations at baseline, 3, 6, 12 months, and 2.5 years. Six participants converted to AD over the follow-up. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the MMSE, CDR-Sum of boxes and Memory z-scores; ROC analyses examined the predictive value for conversion to AD. Results There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, DR, DA) were cross-sectionally correlated with memory z-scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression with likelihood ratios>83, and better than 90% accuracy. Conclusion Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually-drawn fornix ROI shows comparable promise to hippocampal volume as a predictive biomarker of progression and warrants replication in a larger study.

ObjectiveThe assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Materials and MethodsTwenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.ResultsSubstantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).ConclusionsWe identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.