Major Depressive Disorder (MDD) is a complex multifactorial disorder, which would lead to disability. Environmental and genetic factors are involved in MDD etiology. The aim of this project was to identify loci modifying age at onset (AAO) of MDD using survival models after adjusting for Childhood Sexual Abuse (CSA). To achieve this aim, a dataset was made available by the China Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium. The study population had 5,220 controls and 5,282 cases with MDD. We performed two univariate association analyses using Cox Proportional Hazard (Cox PH) models. These two are Full Sample (FS), cases and controls, and only the Case Cohort (CC). No genome-wide significant associations were found in univariate analyses. Subsequent gene set enrichment analysis showed that there were significant enrichments in neurological Gene Ontology terms and some novel non-neural pathways. These findings may allow us to better understand MDD pathology.

Abstract Using three different schizophrenic populations from Northern Finland, gender differences in some sociodemographic variables, age at onset, incidence, treatment, outcome and deinstitutionalization of schizophrenia were examined. The first study population comprises the Northern Finland 1966 Birth Cohort, which is an unselected, general population birth cohort. We followed prospectively 11017 subjects from 16 to 28 years of age by means of the Finnish Hospital Discharge Register. From this study population gender differences at the age of onset and incidence of schizophrenia were calculated. The second study population was formed of 1525 patients who had their first treatment episodes at the closed therapeutic community ward situated at the Department of Psychiatry, University of Oulu during 1977 - 1993. Gender differences were assessed in relation to age at first admission, some sociodemographic variables, degree of active participation of the patients in individual, group, and milieu therapy and institutional outcome of the patients with schizophrenia. The third study population consisted of all the 253 long-stay psychiatric inpatients treated for at least six months without a break during 1992 in the Department of Psychiatry, Oulu University Hospital. From this study population gender differences at the age of onset and in relation to some sociodemographic and clinical variables were studied. The placements after the last discharge and at the end of the follow-up and factors predicting hospitalization after the follow-up were also monitored. There were no statistically significant gender differences regarding age at onset in any of these three different study populations. The time lag between the first psychotic symptoms and the first psychiatric hospitalization was minimal. In the Northern Finland 1966 Birth Cohort study the annual incidence rate of DSM-III-R schizophrenia was relatively high, 7.9 per 10 000 in men and 4.4 in women by the age of 28. In men it was highest in the age group of the 20-24 year-olds while in women the peak occurred earlier in the age group of the 16-19 year-olds. In the Therapeutic community study there were no statistically significant gender differences in the sociodemographic variables, in the length of stay and in the number of treatment episodes in this ward in any of the diagnostic groups. Differences with regard to male and female participation in individual, group and milieu therapy and the institutional outcome were minimal, some trends, however, favoring females. In the long-stay patients study almost two-thirds of these patients were men. Very few gender differences were found in relation to sociodemographic and clinical characteristics or regarding the utilization of psychiatric hospital care. About 70% of the long-stay patients were discharged during the four year follow-up period and only 15% were able to live without continuous support. Marital status (being not married), dwelling place (living in city), absence of negative symptoms and severity of the illness were associated with hospitalization at the end of the follow-up. Gender did not predict hospitalization at the end of the follow-up period. The results of this study indicate that there are probably different subgroups of schizophrenia in which there are no gender differences regarding age at onset and in the clinical picture of the disturbance or there are regional differences in the manifestation of the illness. In Finland patients are hospitalized earlier after the onset of the first psychotic symptoms than in many other countries. According to the Northern Finland 1966 Birth Cohort study the incidence of schizophrenia is higher among young men than women and the total life-time incidence of schizophrenia may be smaller in women. The results from the Therapeutic community study suggest that therapeutic community treatment may level out the gender differences in the treatment process and outcome. The long-stay patient study showed that long-term patients are dependent on considerable support and that the most seriously ill patients are in fact in hospital. Alternative residential facilities have been a presupposition to the deinstitutionalization of the long-stay patients.

Bipolar affective disorder is a very dynamic disease, which is influenced by numerous factors. One of these factors is the age at onset. The age at onset of bipolar affective disorder may play a major role in its course, severity and number of relapses, number of hospitalizations or response to mood stabilizers. Other factors influenced by the age at onset are suicide thoughts or attempted suicide. The aim of this work is to investigate and demonstrate the effect of age of the first symptom on the course of bipolar disorder. In the framework of quantitative research, 116 respondents completed a questionnaire on the course of bipolar affective disorder. Early age at onset (≤ 19 years) correlated significantly with the longer interval between the first symptom and the visit to the doctor, the first symptom and the first diagnosis and the first symptom and the diagnosis of bipolar affective disorder. There were no statistically significant relationships between the age at onset and the number of hospitalizations or the severity of the disease. Although the effect of age at onset on the course and severity of the disease has not been proven, this area should be further explored as it may help to better management the treatment of the disorder.

The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10-5). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.

We performed a genome-wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene×gender interactions for AAO in schizophrenia (SCZ) using a European-American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene×gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P=3.10×10-7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P=4.30×10-6) and the third region was at 4p16.1 (rs17407555, P=4.56×10-6, near RAF1P1, and rs4697924, P=1.23×10-5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P=2.10×10-6 and 2.33×10-6, respectively) and strong gene×gender interactions in influencing AAO (P=9.23×10-7 and 1.15×10-6, respectively) while the second best region showing gene×gender interaction was at 7q22.3 (rs179863, P=2.33×10-6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P<0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ.

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10−6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10−2 and 5.18 × 10−3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10−2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10−4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10−3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10−3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10−3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10−5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p = 8.46 × 10− 4) and 11 SNPs were associated with AAO (top SNP rs1354269 with p = 2.87 × 10− 3). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk (p = 1.7 × 10− 2 and 2.71 × 10− 2; respectively) and AAO (p = 1.85 × 10− 3 and 6.06 × 10− 3; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated. Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (&lt;58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed. Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years. Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-21T12:48:09Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) DISSERTACAO MESTRADO MOYSES PRONTA (1) (1).pdf: 679547 bytes, checksum: cf4dd53c812b868e1a8d7ceb72f62419 (MD5) / Made available in DSpace on 2014-08-21T12:48:09Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) DISSERTACAO MESTRADO MOYSES PRONTA (1) (1).pdf: 679547 bytes, checksum: cf4dd53c812b868e1a8d7ceb72f62419 (MD5) Previous issue date: 2013-09-30 / There are several studies on the differential diagnosis of Bipolar Disorder (BD), however, further investigation with an emphasis on clinical phenotypes that inaugurate the disease is needed. The aims of this study are to identify the psychiatric disorders most frequently diagnosed before the definitive diagnosis of BD, the time until the correct diagnosis and compare BD I and II for the variables studied. We studied 259 patients with current diagnosis of BD according to the DSM- IV-TR, evaluated by the same psychiatrist. Early psychiatric signs and symptoms were identified through an interview with the patient and family members and were considered suggestive of an initial diagnosis that was coded according to the same diagnostic criteria. The authors analyzed data on patients' age at prodromes suggestive of initial psychiatric diagnosis and time delay to the actual diagnosis of BD. Comparisons were made between sex, schooling and type of BD. The mean age of patients was 41.6 years, with a predominance of adults (19-60 years), women (67.6%), as well as type II BD (68.3%). Patients were on average 24.6 years of age at initial diagnosis, 41.6 years in the diagnosis of BD and the mean time delay between these was 16.9 years. The most common initial diagnoses were depressive disorders (41.3%), anxiety (12.7%), ADHD (8.1%), disorders related to substance abuse (7.7%), somatoform disorders (6 9%), and psychosis (5.4%). BD can be considered a “great imitator” in modern psychiatry, since initial phenotypes can mimic other disorders. BD diagnosis is very delayed in Brazil. / Há diversos estudos sobre o diagnóstico diferencial do Transtorno Bipolar (TB), entretanto, investigações com ênfase nos fenótipos clínicos que inauguram a doença são escassos. Os objetivos deste estudo consistem em identificar as doenças psiquiátricas mais frequentemente diagnosticadas antes do diagnóstico definitivo de TB, assim como o intervalo de tempo até o mesmo; e comparar o pacientes com TB I e II quanto aos diagnósticos iniciais, escolaridade, sexo e faixa etária. Para tanto, estudamos 259 pacientes com diagnóstico atual de TB segundo os critérios do DSM-IV-TR, realizado por um mesmo psiquiatra. Através de entrevistas com o paciente e familiares, identificou-se retrospectivamente os sinais e sintomas precoces considerados sugestivos do primeiro diagnóstico psiquiátrico, segundo os mesmos critérios. Dados relativos à idade dos pacientes no diagnóstico inicial e tempo até o diagnóstico atual de TB foram analisados e comparações foram feitas entre sexo, escolaridade, faixa etária e tipo de TB. A média de idade encontrada foi de 41,6 anos, com predominância de adultos (19-60 anos), do gênero feminino (67,6%), com TB II(68,3%). Os pacientes tinham em média 24,6 anos de idade no diagnóstico inicial, 41,6 anos no diagnóstico de TB e o tempo médio de atraso diagnóstico foi de 16,9 anos. Os diagnósticos iniciais mais frequentemente encontrados foram: transtornos depressivos (41,3%), ansiosos (12,7%), TDAH (8,1%), transtornos relacionados ao abuso de substâncias psicoativas (7,7%), transtornos somatoformes (6,9%) e psicóticos (5,4%). O T pode ser considerado um “grande imitador” moderno da Psiquiatria, posto que fenótipos iniciais podem mimetizar outros transtornos. Há um atraso significativo no diagnóstico do TBno Brasil.