Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

miRNAs as therapeutic agents in neurodegeneration, a pilot study

L’échec des différents essais cliniques souligne la nécessité de développer des nouvelles thérapies pour la maladie d’Alzheimer (MA), la cause la plus commune de démence. Les microARNs (miARNs) sont les ARNs non-codants les plus étudiés et ils jouent un rôle important dans la modulation de l’expression des gènes et de multiples voies de signalisation. Des études antérieures, dont celles de mon laboratoire d’accueil, ont permis de développer l’hypothèse que certains membres de la famille miR-15/107 (c.-à-d. miR-15ab, miR-16, miR-195, miR-424, and miR-497) pourraient être utilisés comme agents thérapeutiques dans MA. En effet, cette famille avait le potentiel de réguler de multiples gènes associés à MA, tels que la protéine précurseur de l’amyloïde (APP), la β-secrétase (BACE1), et la protéine Tau. Tel que démontré dans ce projet de thèse, j’ai choisi miR-16 comme cible thérapeutique potentielle pour MA parmi tous les membres de la famille. L’essai luciférase dans ce projet confirme que miR-16 peut réguler simultanément APP et BACE1, directement par une interaction avec la région non-codante en 3’ de l’ARNm). Notamment, nous observons aussi une réduction de la production des peptides amyloïdes et de la phosphorylation de Tau après une augmentation de miR-16 en cellule. J’ai ensuite validé mes résultats in vivo dans la souris en utilisant une méthode de livraison de miR-16 via une pompe osmotique implanté dans le cerveau. Dans ce cas, l’expression des protéines d’intérêts (APP, BACE1, Tau) a été mesurée par immunobuvardage et PCR à temps réel. Après validation, ces résultats ont été complémentés par une étude protéomique (iTRAQ) du tronc cérébral et de l’hippocampe, deux régions associées à la maladie. Ces données m’ont permis d’identifier d’autres protéines régulées par miR-16 in vivo, incluant α-Synucléine, Transferrine receptor1, et SRm300. Une autre observation intéressante : les voies régulées par miR-16 in vivo sont directement en lien avec le stress oxydatif et la neurodégénération. En résumé, ce travail démontre l’efficacité et la faisabilité d’utiliser un miARN comme outil thérapeutique pour la maladie d’Alzheimer. Ces résultats rentrent dans un cadre plus vaste de découvrir de nouvelles cibles pour MA, et en particulier la forme sporadique de la maladie qui représente plus de 95% de tous les cas. Évidemment, la découverte d’une molécule pouvant cibler simultanément les deux pathologies de la maladie (plaques amyloïdes et hyper phosphorylation de tau) est nouvelle et intéressante, et ce domaine de recherche ouvre la porte aux autres petits ARNs non-codants dans MA et les maladies neurodégénératives connexes.

Psychotherapeutic work with Families with Life-threatening Maternal Illness

This exploratory research study describes a child and adolescent psychotherapeutic clinical service offered to children/adolescents and their families with mothers with a life-threatening illness. The clinical service itself was also exploratory in nature. The research objectives of the study were (i) to explore whether this form of clinical work could be beneficial for such families in relieving distress and supporting their development; (ii) to discover the factors at play within and between the family members using an adaptation of Grounded Theory research methodology; and (iii) to add to the knowledge base for adults – family members and professionals – relating to, and dealing with, such children and adolescents. Descriptions and discussion of the therapeutic input and research study are given. Symptoms, which included emotional, behavioural, psychological, learning, and interpersonal difficulties, decreased in all the children/adolescents who were offered clinical treatment within an outpatient multidisciplinary Tier 3 Child and Adolescent Service (CAMHS). Six Themes were identified across the cases and these were named: Engagement, Parental Concern, Impact of Mother’s Illness, Defences, Sustaining Factors and Feeling Different. These Themes are discussed in the light of relevant published research. A literature review was undertaken and focuses on: epidemiological context; children’s understanding of death; impact of parental bereavement in childhood; the mourning process; anticipatory grief; psychoanalysis: mourning and trauma; children’s play and drawings as communication; and psychosocial therapeutic services. The thesis has particular relevance for child and adolescent psychotherapists and other mental health professionals who work within hospital and hospice settings.

Psychotherapeutic work with Families with Life-threatening Maternal Illness

This exploratory research study describes a child and adolescent psychotherapeutic clinical service offered to children/adolescents and their families with mothers with a life-threatening illness. The clinical service itself was also exploratory in nature. The research objectives of the study were (i) to explore whether this form of clinical work could be beneficial for such families in relieving distress and supporting their development; (ii) to discover the factors at play within and between the family members using an adaptation of Grounded Theory research methodology; and (iii) to add to the knowledge base for adults – family members and professionals – relating to, and dealing with, such children and adolescents. Descriptions and discussion of the therapeutic input and research study are given. Symptoms, which included emotional, behavioural, psychological, learning, and interpersonal difficulties, decreased in all the children/adolescents who were offered clinical treatment within an outpatient multidisciplinary Tier 3 Child and Adolescent Service (CAMHS). Six Themes were identified across the cases and these were named: Engagement, Parental Concern, Impact of Mother’s Illness, Defences, Sustaining Factors and Feeling Different. These Themes are discussed in the light of relevant published research. A literature review was undertaken and focuses on: epidemiological context; children’s understanding of death; impact of parental bereavement in childhood; the mourning process; anticipatory grief; psychoanalysis: mourning and trauma; children’s play and drawings as communication; and psychosocial therapeutic services. The thesis has particular relevance for child and adolescent psychotherapists and other mental health professionals who work within hospital and hospice settings.

Undertaking Sensitive Interviews: a Researcher’s Experience of Interviewing Bereaved Parents and Family GPs

The presentation describes the researcher’s experience of undertaking sensitive interviews. Background The interviews form part of a current study that is examining bereaved parents’ experience of caring for their child at home as well as the experience of their GP. This study builds on earlier work that found general practitioners (GPs) were at times uncertain of their role in paediatric palliative care and questioned whether their involvement had been beneficial to the child and family. The rarity of childhood cancer deaths makes it difficult for GPs to develop or maintain palliative care knowledge and skills yet the GP is perceived as the gatekeeper for care within the community. Presentation aim To describe the process of both the preparation for, and undertaking of, sensitive interviews. Study methodology The methodology incorporates tape-recorded semi-structured interviews, thematic framework analysis and Q methodology (QM). QM will be used to capture the experiences of GPs who have cared for a child with cancer receiving palliative care as well the perspectives of care experienced by the families. The semi-structured interview sample comprises 10 families (parents/guardians) whose child has been treated at a regional childhood cancer centre and their GPs. A further 40-60 GPs will be involved in the QM. Findings The preparation for these interviews will be discussed and compared to the supportive bereavement visits undertaken within the researcher’s role as a paediatric Macmillan nurse. The experience of undertaking the interviews will be exemplified with findings from the initial and the current, study. Papers’ contribution The researcher’s experience of preparing for and undertaking sensitive interviews may prove beneficial to other researchers.

Multiresolution analysis (discrete wavelet transform) through Daubechies family for emotion recognition in speech

We propose a study of the mathematical properties of voice as an audio signal -- This work includes signals in which the channel conditions are not ideal for emotion recognition -- Multiresolution analysis- discrete wavelet transform – was performed through the use of Daubechies Wavelet Family (Db1-Haar, Db6, Db8, Db10) allowing the decomposition of the initial audio signal into sets of coefficients on which a set of features was extracted and analyzed statistically in order to differentiate emotional states -- ANNs proved to be a system that allows an appropriate classification of such states -- This study shows that the extracted features using wavelet decomposition are enough to analyze and extract emotional content in audio signals presenting a high accuracy rate in classification of emotional states without the need to use other kinds of classical frequency-time features -- Accordingly, this paper seeks to characterize mathematically the six basic emotions in humans: boredom, disgust, happiness, anxiety, anger and sadness, also included the neutrality, for a total of seven states to identify

Women and work-life balance: a case of austerity and authenticity

Recent evidence suggests that support for gender equality appears to be declining amid concern that women who play a full role in the work force do so at the expense of family life. Although this has been exacerbated by the economic downturn there were pre-recessionary signs of concerns that the welfare of children was being compromised when women find themselves with the double burden of employment and family care. These work-life balance issues are examined from the point of view of looking at how this characterised for women as a problem of authentic self-realisation in terms of working towards and achieving an optimum balance. This kind of dichotomisation allows for different aspects of the self to be pitted against each other: the professional career-orientated aspect and the personal relationship aspect. The paper argues that work-life balance discourse is counter-productive in that it reinforces the inequalities for women that it seeks to redress.

The use of solar colletor for heating and electricity for a single family house

The presented work is related to the use of solar energy for the needs of heating and electricity for a single house located in Poland. Electricity will provided by energy conversion in the turbine by means of Organic Rankine Cycle (ORC), in which the operating medium (water heated in solar collector) is heating refrigerator in the heating exchanger. The solar installation is integrated with heat accumulator and wood boiler, which is used in the situation that collector is not enough to fill requirements of thermal comfort. There are chosen also all the necessary components of the system. In the work is also performed the economic assessment, by F chart method, to evaluate the profitability of the project, taking into total costs and savings.

CAREGIVING FOR A FAMILY MEMBER WITH HEAD AND NECK CANCER

Objective: To know the perception of informal caregivers regarding the care for a family member with head and neck cancer. Methods: Qualitative study conducted between March and May 2014 in the radiotherapy outpatient center of the Centro de Alta Complexidade em Oncologia – CACON (Oncology High Complexity Center) of the Hospital Universitário de Brasília – HUB (University Hospital of Brasília) using semi-structured interviews with nine caregivers about the experience of caring for family members. Data underwent Content Analysis and four units of meaning were identified: “Representation of cancer in the Family”, “The care as debt, individual reward or reconstruction of family ties”, “Repercussions of cancer on the caregiver’s personal life” and “Social support and network used by caregivers”. Results: Feelings of sadness and surprise at the moment of diagnosis were attributed to cancer, as well as the idea of punishment. The care was seen as personal satisfaction, accomplishment and opportunity for family rapprochement. Work overload and change in routine were altered functions. Religiosity, exchange of experience in the waiting room and institutional support appeared as coping strategies. Conclusion: The experience of caring for family members with head and neck cancer directly interferes in the lives of caregivers. Pointing out the institutional embracement as a strategy within the social network reinforces the importance of integrating the caregivers as a significant part of the health care plan developed by the health team.

PERCEPTIONS AND EXPERIENCES OF FAMILY CAREGIVERS OF BEDRIDDEN ELDERLY

Objective: To know the perceptions and experiences of family caregivers of bedridden elderly. Methods: A qualitative descriptive exploratory study conducted in January 2015 with four caregivers in a Family Health Center in the municipality of Araripe, CE. Data were collected through semi-structured interviews and the information was organized using the content analysis technique. A total of three categories emerged from the analysis of the reports of caregivers: the dependence process of the elderly; daily difficulties experienced by the caregiver; and satisfaction with the home care service. Results: The dependence process of the elderly took place as a consequence of pathological processes such as neoplasm, cerebrovascular accident and dementia. However, it could also be observed that physiological phenomena – common in old age – can also make individuals dependent on caregivers. As to the difficulties faced by the caregivers, they reported the need for greater involvement by the family, given that the centralization of work generates an overload and hence affects the care of the elderly. Teamwork in the home care context is fundamental, given that it allows a complementary and comprehensive care to the ledrely/caregiver binomial. Conclusion: Healthy aging is a major challenge to be overcome given that the development of a healthy lifestyle is difficult in all social strata. It is necessary to improve home care in order to provide support to caregivers so that the quality of life of bedridden elderly and caregivers is improved.

Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources

Living Adolescence in Family" parenting program: adaptation and implementation in social and school contexts

Adolescence is a developmental period that implies a series of rapid changes that might complicate the role of parents. This study evaluates changes in parental monitoring and the strategies to solve family conflicts reported by parents who participated in the "Living Adolescence in Family" program in local social services and school centers. In addition, the study analyses the moderating role of family and facilitator variables that may affect the final results. The participants were 697 parents attending the social services (438 in the intervention group and 259 in the control group) and 1283 parents from school centers (880 in the intervention group and 403 in the control group). The results showed that families from local social services decreased the amount of control and improved monitoring in education and leisure spheres as well as self-disclosure whereas the families coming from school centers improved supervision in leisure and in self-disclosure. In addition, both groups of families improved their strategies for solving family conflicts, increasing the use of integrative strategies and decreasing the use of dominant strategies. There were differences across contexts: the results of the program in the social services context differed according to the participant and professional profiles whereas program results were more homogeneous in the school context. In sum, the program appears to be an efficient work tool, both for the professionals who work with at-risk families with adolescents and for the teachers who make use of the program for families with children at risk of early school dropout.

Bis(arylene-ethynylene)-s-tetrazines: A Promising Family of n-Type Organic Semiconductors?

We theoretically describe in this work the n-type semiconducting behavior of a set of bis(arylene-ethynylene)-s-tetrazines ((ArCC)2Tz), by comparing their electronic properties with those of their parent diaryl-s-tetrazines (Ar2Tz) after the introduction of ethynylene bridges. The significantly reduced internal reorganization energy for electron transfer is ascribed to an extended delocalization of the LUMO for (ArCC)2Tz as opposite to that for Ar2Tz, which was described mostly localized on the s-tetrazine ring. The largest electronic coupling and the corresponding electron transfer rates found for bis(phenyl-ethynylene)-s-tetrazine, as well as for some halogenated derivatives, are comparable to those reported for the best performing n-type organic semiconductor materials such as diimides and perylenes. The theoretical mobilities for the studied compounds turn out to be in the range 0.3–1.3 cm2 V–1 s–1, close to values experimentally determined for common n-type organic semiconductors used in real devices. In addition, ohmic contacts can be expected when these compounds are coupled to metallic cathodes such as Na, Ca, and Sm. For these reasons, the future application of semiconducting bis(phenyl-ethynylene)-s-tetrazine and its fluorinated and brominated derivatives in optoelectronic devices is envisioned.

Composite Indicators for the Family Change: ‘Familism' vs ‘Individualism' in the International Context

The aim of this paper is to propose a composite indicator to measure ‘familism’, conformed by two main dimensions: values on one hand (duty to take care of the family, importance of the family, sacrifices for the family...) and behaviours, on the other (predominance of married couples instead of cohabitant couples, high frequency of contact among members, family support…). In contrast to this idea of ‘familism’ we find that of individualism, that defends the independence of family members, tolerance to new family models, cohabitation instead of marriage,… , that implies less frequency of interaction among relatives and more governmental intervention towards children and elderly care. We observe that a higher degree of ‘familism’ does not always match with a lower degree of individualism when both dimensions, attitudes and behaviours, are considered. For instance, we find countries which are individualist in values but not in behaviours (such as Spain), whilst others, such as Japan, are ‘familist’ both in values and behaviours and finally, others, such as Sweden, are individualist with regards to both perspectives. We propose two different methodological approaches to the question. First, we use microdata from the Family, Work and Gender Roles module of the International Social Survey Programme-ISSP (years 1994, 2002 and 2012), in which 45 countries have participated. Information for the three rounds is collected for 17 countries with very different family values and welfare systems (for instance, Sweden, Japan, Russia, Spain, United Kingdom or the United States). From this data source, we create a first index on familism that can be related to individual sociodemographic characteristics. Second, we complete it through the inclusion of macro data (such as the divorce rate per country), in order to refine comparison at a country level by adding new variables to the previous index.

Composite Indicators for the Family Change: ‘Familism' vs ‘Individualism' in the International Context

The aim of this paper is to propose a composite indicator to measure ‘familism’, conformed by two main dimensions: values on one hand (duty to take care of the family, importance of the family, sacrifices for the family...) and behaviours, on the other (predominance of married couples instead of cohabitant couples, high frequency of contact among members, family support…). In contrast to this idea of ‘familism’ we find that of individualism, that defends the independence of family members, tolerance to new family models, cohabitation instead of marriage,… , that implies less frequency of interaction among relatives and more governmental intervention towards children and elderly care. We observe that a higher degree of ‘familism’ does not always match with a lower degree of individualism when both dimensions, attitudes and behaviours, are considered. For instance, we find countries which are individualist in values but not in behaviours (such as Spain), whilst others, such as Japan, are ‘familist’ both in values and behaviours and finally, others, such as Sweden, are individualist with regards to both perspectives. We propose two different methodological approaches to the question. First, we use microdata from the Family, Work and Gender Roles module of the International Social Survey Programme-ISSP (years 1994, 2002 and 2012), in which 45 countries have participated. Information for the three rounds is collected for 17 countries with very different family values and welfare systems (for instance, Sweden, Japan, Russia, Spain, United Kingdom or the United States). From this data source, we create a first index on familism that can be related to individual sociodemographic characteristics. Second, we complete it through the inclusion of macro data (such as the divorce rate per country), in order to refine comparison at a country level by adding new variables to the previous index.