Many complex diseases are known to have a substantial genetically heritable component. Elucidation of these genetic risk factors provides increased knowledge of the biological mechanisms that result in the diseases while also presenting new potential targets for therapy. This thesis explores the methodology of mapping genetic loci using isolated populations in the context of quantitative trait analysis. Chapter 1 explores the rational for the project, discussing the benefits of using quantitative traits rather than binary disease status and the pros and cons of using isolated populations. This is followed by a brief history of genetic mapping with reference to type 2 diabetes mellitus (T2D) and related quantitative traits. Chapter 2 introduces the methods used in this thesis. This includes strategies to deal with medication, methods to determine kinship between individuals, linkage analysis, association analysis and meta‐analysis of multiple studies. Chapter 3 presents linkage analysis of T2D related traits carried out in 2 – 4 populations depending on availability of the traits and appropriate marker data. Chapter 4 presents the results of association analysis for T2D related traits in 3 – 5 populations using genome‐wide SNP data. The results using the alternate methods described in chapter 2 are compared using fasting glucose as this was the most widely measured phenotype. Chapter 5 introduces additional traits derived by pulse wave analysis and discusses their relevance to metabolic disease before presenting association analysis using the preferred method from chapter 4. An overall discussion of the strengths and weaknesses of the analysis is given in chapter 6.

Background Affective disorders are poorly defined and studied in sub-Saharan Africa despite their substantial public health impact. Objectives Overall objective: To describe the epidemiology of selected affective disorders in rural Ethiopia. Specific objectives 1. To describe the validity and utility of the concept of minor depressive disorder (mD). 2. To describe the manifestation, prevalence and the short-term clinical and functional course and outcome of bipolar disorder. Subjects and methods Population: Zay community residents (age ≥16), and residents of Butajira (ages 15-49), in Southern Ethiopia. Study design: Population-based cross-sectional and longitudinal studies Case identification: For the identification of cases with bipolar disorder, a two stage process was employed. An initial screen used key informants and interview with the Composite International Diagnostic Interview (CIDI) to identify cases with probable bipolar disorder. A second confirmatory diagnostic assessment stage employed the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). For the identification of cases with mD, data from the CIDI was used. Follow-up: 312 cases with bipolar disorder from Butajira were followed up for a mean of 2.5 years (ranging 1-4 years) through monthly clinical assessments and annual symptom and functional ratings. Results The CIDI was administered to 1714 adults among the Zay and to 68, 378 adults among the Butajira residents. The prevalence of mD among the Zay and Butajira was 20.5% and 2.2% respectively. Up to 80% of cases with mD had used services for their symptoms, while a third to a half of cases had thought about self harm. Up to a sixth of cases had attempted suicide. Age, marital status, education and somatic symptoms were independently associated with mD. The prevalence of bipolar disorder among the Zay was 1.8%. During a 2.5-year follow-up of 312 cases with bipolar disorder from Butajira, 65.9% relapsed (47.8% manic, 44.3% depressive and 7.7% mixed episodes) while 31.1% experienced persistent illness. Female gender predicted depressive relapse whereas male gender predicted manic relapse. Only being on psychotropic medication predicted remission (OR=3.42; 95% CI=1.82, 6.45). Disability was much worse among bipolar patients than in the general population and was predicted by symptom se3verity. Conclusions This is the largest study on mD and bipolar disorder in Africa. mD appears to have potential clinical utility in this setting given its association with service use and risk. The identified risk factors for mD also suggest potential aetiological continuity with major depression. The relatively high prevalence of bipolar disorder among the Zay may be related to genetic predisposition perhaps mediated through a founder effect, but other factors need exploring. In relation to the outcome of bipolar disorder, this study indicates that, contrary to previous assumptions, the course of bipolar disorder is characterised by both manic and depressive relapses in a relatively proportionate fashion. Bipolar disorder also leads to significant levels of disability. This is the only prospective outcome study of bipolar disorder in Africa where cases were monitored systematically at short assessment intervals. Therefore, findings are likely to be more robust than previous reports.

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Objetivo: este estudo teve por objetivo verificar a eficácia de um procedimento para a identificação da deficiência auditiva em crianças pré escolares de uma comunidade de baixa renda por pessoas não especialistas. Casuística e métodos: funcionários da creche e da unidade de saúde foram treinados para aplicarem um questionário para triagem auditiva nos pais de 224 crianças de 3 a 6 anos de idade, que foram submetidas à triagem audiométrica e imitanciométrica. Resultados: verificou-se alta concordância na coleta de dados por meio do questionário entre a pesquisadora e os não especialistas. O questionário apresentou melhor sensibilidade e pior especificidade. Os não especialistas relataram aprendizado com a pesquisa e conscientização sobre a importância da audição. Conclusão: é possível treinar agentes comunitários a identificarem a deficiência auditiva em suas comunidades com instrumentos de baixo custo. / Aim: this study aimed to access the efficacy of a low cost instrument used by non professionals to identify hearing loss in pre-school children in a low income community. Methods: employees of a nursery school and a health unit were trained to use a hearing screening questionnaire with parents of 224 children aged 3 to 6 years. The children underwent audiological screening. Results: the results showed that the non - specialists were capable of reproducing the evaluation of the professional regarding the use of the questionnaire. The questionnaire presented better sensitivity than specificity. The non - specialists reported learning and awareness of the importance of hearing in children. Conclusion: the questionnaire offers a low cost option for hearing screening, specially if it is administered by non professionals resources

Objetivo: este estudo teve por objetivo verificar a eficácia de um procedimento para a identificação da deficiência auditiva em crianças pré escolares de uma comunidade de baixa renda por pessoas não especialistas. Casuística e métodos: funcionários da creche e da unidade de saúde foram treinados para aplicarem um questionário para triagem auditiva nos pais de 224 crianças de 3 a 6 anos de idade, que foram submetidas à triagem audiométrica e imitanciométrica. Resultados: verificou-se alta concordância na coleta de dados por meio do questionário entre a pesquisadora e os não especialistas. O questionário apresentou melhor sensibilidade e pior especificidade. Os não especialistas relataram aprendizado com a pesquisa e conscientização sobre a importância da audição. Conclusão: é possível treinar agentes comunitários a identificarem a deficiência auditiva em suas comunidades com instrumentos de baixo custo. / Aim: this study aimed to access the efficacy of a low cost instrument used by non professionals to identify hearing loss in pre-school children in a low income community. Methods: employees of a nursery school and a health unit were trained to use a hearing screening questionnaire with parents of 224 children aged 3 to 6 years. The children underwent audiological screening. Results: the results showed that the non - specialists were capable of reproducing the evaluation of the professional regarding the use of the questionnaire. The questionnaire presented better sensitivity than specificity. The non - specialists reported learning and awareness of the importance of hearing in children. Conclusion: the questionnaire offers a low cost option for hearing screening, specially if it is administered by non professionals resources