Genetic association studies of bipolar disorder.

Bipolar disorder is a common and serious mental illness. The occurrence of mania is central to the diagnosis, but affected individuals typically also suffer episodes of depression. The results of family, twin and adoption studies argue convincingly for genetic susceptibility to bipolar disorder. Linkage studies conducted at the Molecular Psychiatry Laboratory, UCL have previously implicated the regions 12q24, 21q22, lq42 and 11 pi4- 15 as harbouring susceptibly loci for bipolar disorder. In this thesis I report fine mapping of the 12q24, 21q22 and lq42 regions by linkage disequilibrium methods, employing a case-control design. For the llpl4-15 region association with the candidate gene BDNF was tested. I also present attempts to replicate findings of association at the genes DAOA and COMT, located in regions implicated by meta-analysis of the linkage data. I have attempted to put these investigations in context, necessitating consideration of the conceptual developmental of bipolar disorder, the classical techniques for assessing the genetic contribution to aetiology, and mapping strategies. Fine mapping of the UCL linkage regions implicated two novel susceptibility loci and provided support for two previously identified loci. Association of multiple markers within a 180 kb region of 12q24.3 was found, implicating Slynar and LOC387895. Association was also found with two markers in the more centromeric gene P2RX7, previously implicated in a Canadian sample. Multiple associated markers were found on 21q22.3. Two candidate genes - C21orf29 and TRPM2 - were identified from this region. Initial efforts to fine map the lq42 region suggested the involvement of the previously implicated DISCI gene. However association was only found with a single marker. Although haplotypic association was found with BDNF, the complex structure of the microsatellite marker hindered interpretation of the results. Partial replication of the association with DAOA was achieved but the involvement of COMT was not supported

Knockdown of the C. elegans kinome identifies kinases required for normal protein homeostasis, mitochondrial network structure, and sarcomere structure in muscle

Kinases are important signalling molecules for modulating cellular processes and major targets of drug discovery programs. However, functional information for roughly half the human kinome is lacking. We conducted three kinome wide, >90%, RNAi screens and epistasis testing of some identified kinases against known intramuscular signalling systems to increase the functional annotation of the C. elegans kinome and expand our understanding of kinome influence upon muscle protein degradation

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

MAGNETOOPTICS OF (Ga, In) As QUANTUM WELLS : EXCITON BINDING ENERGIES AND CARRIER EFFECTIVE MASSES

Transmission measurements, in magnetic fields of up to 16T, have been performed on a series of undoped (Ga,In)As-InP quantum wells. Transitions with Landau indices up to l=15 and energies up to 400meV above Eg are seen. A fit of the experimental data to a theoretical model for excitons at high magnetic fields in very anisotropic systems allows us to deduce values for the carrier effective masses, the electron non-parabolicity and the exciton binding energy