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

Complex genetic approaches to neurodegenerative diseases.

Neurodegenerative diseases are fatal disorders in which disease pathogenesis results in the progressive degeneration of the central and/or the peripheral nervous systems. These diseases currently affect -2% of the population but are expected to increase in prevalence as average life expectancy increases. The majority of these diseases have a complex genetic basis. The work presented in this thesis aimed to investigate the genetic basis of two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and the human prion diseases kuru and sporadic Creutzfeldt-Jakob disease (sCJD), using novel complex genetic approaches. ALS is a fatal neurodegenerative disease in which motor neurons are seen to degenerate. It is a complex disease with 10% of individuals having a family history and the remaining 90% of non-familial cases having some genetic component. The gene DYNC1H1 is involved in retrograde axonal transport and is a good candidate for ALS. In this thesis the genetic architecture of DYNC1H1 was elucidated and a mutation screen of exons 8, 13 and 14 was undertaken in familial forms of ALS and other motor neuron diseases. No mutations were found. A linkage disequilibrium (LD) based association study was conducted using two tagging single nucleotide polymorphisms (tSNPs) which were identified as sufficient to represent genetic variation across DYNC1HI. These tSNPs were tested for an association with sporadic ALS (SALS) in 261 cases and 225 matched controls but no association was identified. Kuru is a devastating epidemic prion disease which affected a highly geographically restricted area of the Papua New Guinea highlands, predominantly affected adult women and children. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism, in the late 1950's. Kuru imposed strong balancing selection on codon 129 of the prion gene (PRNP). Analysis of kuru-exposed and unexposed populations showed significant deviations from Hardy-Weinberg equilibrium (HWE) consistent with the known protective effect of codon 129 heterozygosity. Signatures of selection were investigated in the surviving populations, such as deviations from HWE and an increasing cline in codon 129 valine allele frequency, which covaried with disease exposure. A novel PRNP G127V polymorphism was detected which, while common in the area of highest kuru incidence, was absent from kuru patients and unexposed population groups. Genealogical analysis revealed that the heterozygous PRNP G127V genotype confers strong prion disease resistance, which has been selected by the kuru epidemic. Finally, PRNP copy number was investigated as a possible genetic mechanism for susceptibility to kuru and sCJD. No conclusive copy number changes were identified

The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs

A linkage study of a qualitative disease endophenotype in a sample of sib pairs, consisting of one disease affected proband and one sibling is considered. The linkage statistic compares marker allele sharing with the proband in siblings with an abnormal endophenotype to siblings with the normal endophenotype. Expressions are derived for the distribution of this linkage statistic, in terms of the recombination fraction and (1) the genetic parameter values (allele frequency and endophenotype and disease penetrance) and (2) the abnormal endophenotype rates in the population and in classes of relatives of disease affected probands. It is then shown that when either the disease or the abnormal endophenotype has additive penetrance, the expressions simplify to a monotonic function of the difference between abnormal endophenotype rates in siblings and in the population. Thought disorder is considered as a putative schizophrenia endophenotype. Forty sets of genetic parameter values that correspond to the known prevalence values for thought disorder in schizophrenic patients, siblings of schizophrenics and the general population are evaluated. For these genetic parameter values, numerical results show that the test statistic has >70% power ([alpha]=0.0001) in general with a sample of 200 or more proband-sibling pairs to detect linkage between a marker ([theta]=0.01) and a locus pleiotropic for schizophrenia and thought disorder.

The philosophy of behavioural genomics: analysis of criteria for the conceptual mapping of research in the genomics of human behaviour

This is a philosophical enquiry into scientific research that studies the causes of behaviour, principally human, using the findings, techniques or tools of genomic science. The objectives, concepts and methods of eight selected disciplines are analysed: biomolecular archaeology, evolutionary biomechanics, molecular neurobiology, Down syndrome research, human behavioural ecology, behavioural genetics, human evolutionary genetics and human developmental genetics. Nine semi-structured interviews were conducted with leading researchers in these fields. The results are analysed in terms of a set of fourteen criteria, chosen to illustrate diversity in the conceptual approaches of the researchers concerned. Some of these, for example, put the accent in their work on phylogeny rather than ontogeny. Some study the action of nuclear genes; some concentrate on mitochondrial DNA. The results are also plotted in a Criterion Matrix. The researchers spoke as individuals, not as representatives of their discipline. In parallel, sources in the literature as well as the interviews were used to generate a Genomic Workbench Analysis Model, identifying the different regions of the human and other genomes used by different disciplines in their research. The process of enquiry is presented as a conceptual mapping of the putative field of behavioural genomics. The two principal tools of the method – the Criterion Matrix and the Genomic Workbench Analysis Model – convey a picture of rich and complex diversity among the target disciplines. It is concluded that this diversity is inconsistent with a two-clusters model such as might have been suggested in the past by a polarisation of the nature-nurture debate along a single axis. Other conclusions of the conceptual mapping study are presented. A suggestion is made for the future development of a field of behavioural environomics.The research was conducted under the auspices of the Economic and Social Research Council (ESRC) Centre for Genomics and Society (Egenis). It was partly funded by the Professional Training Unit of the European Parliament