Alcohol dependence (AD) is a serious and common public health problem that contributes to great societal, medical, and legal costs. It has taken work from multiple disciplines, including developmental psychology, genetic epidemiology, and molecular genetics, to achieve our current understanding of environmental and genetic risk factors for AD as well as its variable developmental trajectories. Nevertheless, there is still much to be learned in order to improve treatment outcomes. One approach to augmenting our understanding of this disorder is through genetically informative study designs that either examine risk in aggregate or assess specific susceptibility variants. In this dissertation, we utilize both study designs and provide support for the idea that they are both important and useful approaches to continue to pursue.

Les traits d’insensibilité émotionnelle, tels le manque d’empathie, le manque de remords et l’affect superficiel, sont corrélés avec les troubles de comportement chez les jeunes. La recherche suggère que les traits d’insensibilité émotionnelle et les troubles de comportement sont influencés par des facteurs génétiques communs, et pourraient aussi être influencés, du moins en partie, par des facteurs environnementaux communs. Bien que travaux antérieurs suggèrent que les traits d’insensibilité émotionnelle soient positivement (p. ex., hyperactivité) ou négativement (p. ex., anxiété) associés à d’autres symptômes de psychopathologie, les études portant sur les facteurs étiologiques communs aux traits d’insensibilité émotionnelle et ces autres symptômes de psychopathologie sont plus limitées. Objectifs. Nous proposons d’examiner les associations étiologiques entre les traits d’insensibilité émotionnelle et 1) les troubles de comportement, 2) l’hyperactivité, et 3) l’anxiété, à l’aide d’un échantillon de jumeaux. Méthode. Les participants sont 204 paires complètes et 18 paires incomplètes de jumeaux de même sexe (n = 426; 42% filles; 43% MZ; âge = 15 ans) issus du Child and Adolescents Twin Study in Sweden, une étude longitudinale composée de jumeaux suédois. Des mesures auto-révélées ont été utilisées pour évaluer les traits d’insensibilité émotionnelle, les troubles de comportement, l’hyperactivité et l’anxiété. Des modèles d’équations structurelles ont été estimés afin d’évaluer les contributions génétiques et environnementales des traits d’insensibilité émotionnelle ainsi que leur chevauchement étiologique avec les troubles de comportement, l’hyperactivité et l’anxiété. Résultats. Nous avons trouvé une corrélation génétique forte et positive entre les traits d’insensibilité émotionnelle et les troubles de comportement, mais aucune corrélation significative sur le plan des facteurs environnementaux. Nous avons trouvé une corrélation génétique modérée entre les traits d’insensibilité émotionnelle et l’hyperactivité. Nous avons également trouvé une corrélation génétique modeste et négative entre les traits d’insensibilité émotionnelle et l’anxiété. Conclusion. Ces résultats suggèrent l’existence de facteurs génétiques communs expliquant les traits d’insensibilité émotionnelle et les troubles de comportement, plus particulièrement, et dans une moindre mesure les traits d’insensibilité émotionnelle et l’hyperactivité. En outre, les résultats suggèrent que des facteurs génétiques contribuant à la présence de traits d’insensibilité émotionnelle contribueraient aussi à la diminution des symptômes d’anxiété. / Callous-unemotional (CU) traits, such as lack of empathy, lack of guilt and shallow affect, are associated with conduct problems in youth. Research suggests that CU traits and conduct problems share common genetic factors and, possibly environmental factors. Despite evidence for a behavioural association between CU traits and hyperactivity and between CU traits and low anxiety, the etiological associations between these pairs have been considerably less explored. Objectives. Using a twin model-fitting approach, we investigated the etiological associations between CU traits and 1) conduct problems, 2) hyperactivity and 3) anxiety. Method. Participants were 204 complete pairs and 18 incomplete pairs of same-sex twins (n = 426; 42% female; 43% MZ; age = 15) drawn from the Child and Adolescents Twin Study in Sweden, a longitudinal study of twins born in Sweden. CU traits, conduct problems, hyperactivity and anxiety were assessed through self-reports. Structural equation modeling was used to conduct model-fitting analyses. Results. We found a strong positive genetic correlation between CU traits and conduct problems but no significant environmental correlations. We found a moderate genetic correlation between CU traits and hyperactivity. We also found a modest but significant negative genetic correlation between CU traits and anxiety. Conclusion. These findings suggest that common genetic factors explain CU traits and conduct problems, more particularly, and to a lesser extent CU traits and hyperactivity. In addition, these findings suggest that some of the genetic factors contributing to CU traits may also contribute to decreasing levels of anxiety.

Background:  Previous research have found that different factors have associations with the level of function. Only few studies investigate the population of older adults with movement disabilities.  Objective: The objective was to investigate how childhood socioeconomic status, education, gender, rural/urban living, and cohort affects functioning in late adulthood for people with movement disabilities. Six hypotheses were tested.  Method: The sample was selected from the Swedish Adoption/Twin Study of Aging, and consisted of n=69 older adults with self-reported movement disability, mean age 78 years. They have all participated in motor function testing, which is an objective measure of function. Mann-Whitney U test, Kruskal-Wallis H test and binary logistic regressions were performed.  Result: No significant difference were found between low/high childhood socioeconomic status, low/high education, men/women, rural/urban, and early/late cohort. Associations were found between age, urban living, later cohort and poorer functional level.  Conclusion: The results indicate that the older adults from Sweden aging with a movement disability might have equal opportunity to develop and maintain functional ability. The participants all have a movement disability and it is possible that the disability is the main factor determining the functional level.

Abstract Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied further. / Tiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan.

Abstract The use of 3D imaging of craniofacial soft tissue has increased in medical science, and imaging technology has been developed greatly in recent years. 3D models are quite accurate and with imaging devices based on stereophotogrammetry, capturing the data is a quick and easy operation for the subject. However, analyzing 3D models of the face or head can be challenging and there is a growing need for efficient quantitative methods. In this thesis, new mathematical methods and tools for measuring craniofacial structures are developed. The thesis is divided into three parts. In the first part, facial 3D data of Lithuanian twins are used for the determination of zygosity. Statistical pattern recognition methodology is used for classification and the results are compared with DNA testing. In the second part of the thesis, the distribution of surface normal vector directions of a 3D infant head model is used to analyze skull deformation. The level of flatness and asymmetry are quantified by functionals of the kernel density estimate of the normal vector directions. Using 3D models from infants at the age of three months and clinical ratings made by experts, this novel method is compared with some previously suggested approaches. The method is also applied to clinical longitudinal research in which 3D images from three different time points are analyzed to find the course of positional cranial deformation and associated risk factors. The final part of the thesis introduces a novel statistical scale space method, SphereSiZer, for exploring the structures of a probability density function defined on the unit sphere. The tools developed in the second part are used for the implementation of SphereSiZer. In SphereSiZer, the scale-dependent features of the density are visualized by projecting the statistically significant gradients onto a planar contour plot of the density function. The method is tested by analyzing samples of surface unit normal vector data of an infant head as well as data from generated simulated spherical densities. The results and examples of the study show that the proposed novel methods perform well. The methods can be extended and developed in further studies. Cranial and facial 3D models will offer many opportunities for the development of new and sophisticated analytical methods in the future. / Tiivistelmä Pään ja kasvojen pehmytkudoksen 3D-kuvantaminen on yleistynyt lääketieteessä, ja siihen tarvittava teknologia on kehittynyt huomattavasti viime vuosina. 3D-mallit ovat melko tarkkoja, ja kuvaus stereofotogrammetriaan perustuvalla laitteella on nopea ja helppo tilanne kuvattavalle. Kasvojen ja pään 3D-mallien analysointi voi kuitenkin olla haastavaa, ja tarve tehokkaille kvantitatiivisille menetelmille on kasvanut. Tässä väitöskirjassa kehitetään uusia matemaattisia kraniofakiaalisten rakenteiden mittausmenetelmiä ja -työkaluja. Työ on jaettu kolmeen osaan. Ensimmäisessä osassa pyritään määrittämään liettualaisten kaksosten tsygositeetti kasvojen 3D-datan perusteella. Luokituksessa hyödynnetään tilastollista hahmontunnistusta, ja tuloksia verrataan DNA-testituloksiin. Toisessa osassa analysoidaan pään epämuodostumia imeväisikäisten päiden 3D-kuvista laskettujen pintanormaalivektorien suuntiin perustuvan jakauman avulla. Tasaisuuden ja epäsymmetrian määrää mitataan normaalivektorien suuntakulmien ydinestimaatin funktionaalien avulla. Kehitettyä menetelmää verrataan joihinkin aiemmin ehdotettuihin lähestymistapoihin mittaamalla kolmen kuukauden ikäisten imeväisten 3D-malleja ja tarkastelemalla asiantuntijoiden tekemiä kliinisiä pisteytyksiä. Menetelmää sovelletaan myös kliiniseen pitkittäistutkimukseen, jossa tutkitaan pään epämuodostumien ja niihin liittyvien riskitekijöiden kehitystä kolmena eri ajankohtana otettujen 3D-kuvien perusteella. Viimeisessä osassa esitellään uusi tilastollinen skaala-avaruusmenetelmä SphereSiZer, jolla tutkitaan yksikköpallon tiheysfunktion rakenteita. Toisessa osassa kehitettyjä työkaluja sovelletaan SphereSiZerin toteutukseen. SphereSiZer-menetelmässä tiheysfunktion eri skaalojen piirteet visualisoidaan projisoimalla tilastollisesti merkitsevät gradientit tiheysfunktiota kuvaavalle isoviivakartalle. Menetelmää sovelletaan imeväisikäisen pään pintanormaalivektoridataan ja simuloituihin, pallotiheysfunktioihin perustuviin otoksiin. Tulosten ja esimerkkien perusteella väitöskirjassa esitetyt uudet menetelmät toimivat hyvin. Menetelmiä voidaan myös kehittää edelleen ja laajentaa jatkotutkimuksissa. Pään ja kasvojen 3D-mallit tarjoavat paljon mahdollisuuksia uusien ja laadukkaiden analyysityökalujen kehitykseen myöhemmissä tutkimuksissa.

Contexte : Bien qu’il ait été proposé que l’exposition à un faible statut socioéconomique (SSE) familial altère l’activité de l’axe hypothalamo-pituito-surrénalien et sa production de l’hormone cortisol, les résultats actuels sont incohérents et suggèrent la présence de facteurs supplémentaires susceptibles de modifier ces associations. Pourtant, peu d’études à ce jour ont adopté une approche développementale sensible au timing, à la stabilité et aux changements au sein du SSE familial lors de l’étude de l’association liant le SSE au cortisol. En outre, peu de travaux empiriques ont évalué si cette association est non linéaire ou si elle est modulée par le soutien social. Enfin, rares sont les études qui ont examiné dans quelle mesure cette association est affectée par les facteurs génétiques et par les processus gène-environnement, notamment à l’adolescence. Objectifs : Ancré dans une perspective de psychopathologie développementale, l’objectif principal de cette thèse est d’examiner les processus gène-environnement impliqués dans les associations entre le SSE et divers indicateurs de sécrétion cortisolaire mesurés à l’adolescence. Cette thèse a également examiné dans quelle mesure ces associations sont affectées par le timing, la chronicité et les changements au sein du SSE familial et sont atténuées par le soutien social. Méthodes : Les participants proviennent de l’Étude des jumeaux nouveau-nés du Québec, un échantillon populationnel de jumeaux recrutés à la naissance. Le SSE familial a été recueilli au cours de la petite enfance (0-5 ans) et à la mi-adolescence (14 ans). Le soutien social a été rapporté par les jumeaux à l’âge de 14 et de 19 ans. Le cortisol diurne (n=569) a été mesuré à l’âge de 14 ans au réveil, 30 minutes plus tard, l’après-midi et le soir pendant quatre jours non consécutifs. Le cortisol capillaire (n=704) a été mesuré à l’âge de 19 ans. Résultats : Cette thèse est composée de trois articles. Les résultats des deux premiers articles indiquent que l’étiologie génétique du cortisol au réveil et capillaire fluctuent au long du continuum du SSE mesuré à la petite enfance. Les formes que prennent ces interactions gène-environnement sont toutefois distinctes pour ces indicateurs. De plus, nos résultats révèlent la présence d’associations uniques entre le SSE familial mesuré à la mi-adolescence et la plupart des indicateurs cortisolaire, soit suivant une relation linéaire, ou non linéaire. Nous avons également trouvé que l’association liant le SSE au cortisol capillaire n’est pas expliquée par une étiologie génétique commune, mais semble refléter les effets de l’environnement partagé par les jumeaux. Enfin, les résultats du troisième article suggèrent que l’effet synergique du SES familial mesuré à la petite enfance et à la mi-adolescence prédisent la sécrétion cortisolaire. De plus, l’association concomitante entre le SSE et le cortisol au réveil est modulée par le soutien social. Conclusions : Collectivement, ces résultats soulignent l’importance d’adopter une approche développementale et génétiquement informative lors de l’étude de l’association liant l’adversité aux systèmes physiologiques de stress. Un tel examen pourrait contribuer à une meilleure compréhension des mécanismes sous-tendant les disparités socioéconomiques précoces documentées en matière de santé, d’apprentissage et de comportements. / Background: While exposure to lower family socioeconomic status (SES) has been proposed to induce alterations in hypothalamic-pituitary-adrenal (HPA) axis activity and its production of the hormone cortisol, existing findings are inconsistent and suggest the presence of additional factors that may modify these associations. Yet, few of the past studies have taken a developmental approach sensitive to the timing, stability, and change within family SES when investigating the association between SES and cortisol secretion. Furthermore, little empirical attention has been devoted to assessing the possibility that this association might be nonlinear or is modulated by youth’s perceived availability of social support. Lastly, the extent to which this association is affected by genetic factors as well as gene-environmental interplays has seldom been investigated, particularly in adolescence. Objectives: Rooted in a developmental psychopathology perspective, the present thesis’s main objective is to examine the gene-environment processes implicated in the associations of family SES with multiple indicators of cortisol secretion during adolescence. This thesis also investigated to what extent these associations are affected by the timing, chronicity and change in SES and buffered by perceived social support. Methods: Participants are from the Québec Newborn Twin Study, a population-based sample of twin pairs recruited at birth. Family SES was collected in early childhood (ages 0–5) and mid-adolescence (age 14). Perceived social support was reported by twins at aged 14 and 19. Diurnal cortisol (n=569) was measured at age 14 at awakening, 30 min later, in the afternoon and evening over four non-consecutive days. Hair cortisol (n=704) was measured at age 19. Results: This thesis is comprised of three articles. The results of the first two papers indicate that the genetic etiology of adolescence awakening cortisol and HCC fluctuated along the continuum of early childhood family SES. The patterns of these gene-environment interactions were, however, distinct for these indicators. Furthermore, our results pointed to unique associations between mid-adolescence family SES and most of the diurnal and hair cortisol indicators, either according to a linear or nonlinear function. We also found that the association linking mid-adolescence family SES to HCC is not explained by a common genetic etiology but appears to reflect shared environmental effects. Finally, the results of the third paper revealed that the synergistic effect of early childhood and mid-adolescence SES predicted cortisol secretion. Moreover, the concomitant association between SES and awakening cortisol was found to be modulated by mid-adolescence social support. Conclusions: Collectively, these findings underscore the necessity of espousing a developmental and genetically sensitive approach in studies investigating the impact of adversity on stress physiological systems. Such investigations may pave the way to a fuller understanding of the mechanisms underlying the early roots of socioeconomic disparities in health, learning and behaviours.

Die vorliegende Dissertation untersucht die Relevanz von Kontrollüberzeugungen in der intergenerationalen Transmission von sozialem Status. Motiviert ist die Arbeit von der Frage nach der Möglichkeit Chancengerechtigkeit durch die Verringerung herkunftsbedingter Unterschiede in Kontrollüberzeugungen zu erhöhen. Nach einer Einführung des zentralen Konstruktes werden im theoretischen Teil durch die Zusammenführung soziologischer und sozialpsychologischer Theorien potentielle Transmissionsmechanismen erörtert. Der empirische Teil prüft den postulierten Transmissionskanal anhand längsschnittlicher Daten. Um die Möglichkeit der Verringerung herkunftsbedingter Unterschiede in Kontrollüberzeugungen abzuschätzen wurde mit Hilfe von Zwillingsdaten und einer randomisiert kontrollierten Interventionsstudie untersucht wie stark Kontrollüberzeugung genetisch determiniert sind beziehungsweise von sozialen Faktoren innerhalb und außerhalb des familiären Kontextes beeinflusst werden. Die Ergebnisse deuten darauf hin, dass Kontrollüberzeugungen den Einfluss des Herkunftsstatus auf den eigenen Status teilweise mediieren. In Übereinstimmung mit bisherigen Studien weisen die Ergebnisse der Zwillingsstudien darauf hin, dass Kontrollüberzeugungen in hohem sozial determiniert sind. Die Interventionsstudie indiziert ,dass Kontrollüberzeugungen gezielt verändert werden können. Im konkreten Fall konnten externe, fatalistische Kontrollüberzeugungen durch ein Mentoringprogramm verringert werden. Abschließend wird die gesellschaftliche Norm zur Internalität kritisch betrachtet. Sowohl internale als auch externale Kontrollüberzeugungen können adaptiv sein, sofern sie auf realistischen Einschätzungen der tatsächlich vorhandenen Kontrollmöglichkeiten basieren. Die Grenzen der tatsächlich vorhanden Kontrollmöglichkeiten zu erforschen und zu benennen wird als wichtiges Ziel soziologischer Forschung in diesem Bereich herausgestellt. / This dissertation aims to assess the role of locus of control (LoC) in the intergenerational transmission of social status as well as the potential to raise fair equality of opportunity by reducing the social gradient in LoC. After the core concept of locus of control is introduced, the theoretical part explicates the mechanisms through which social status is likely to be reproduced via LoC across generations. Structural equation modeling is used to assess the substantive importance of LoC in the intergenerational reproduction of social status using data from the British Cohort Study 1970. The evidence suggests that LoC partly mediates the influence of parents’ status on own status attainment: Children from low-SES households are less likely to be endowed with the type of LoC that benefits status attainment later in life. Hence LoC is a potential lever for reducing intergenerational status persistence. As the potency of this lever depends on the degree to which LoC is socially formed rather than genetically determined another aim was to provide evidence on the contribution of genetic inheritance and different social actors at different points in the life-span. Towards this end, information from a multi-cohort twin study and a randomized controlled intervention study were analyzed. The evidence suggests that extra-familial influences become more important in determining locus of control across age, and that a low-intensity mentoring program can reduce fatalistic LoC in low-status children, but not their overall locus of control. The overall discussion reflects upon a general social norm of internality. It is argued that internality and externality are functional if they are based on a realistic assessment of the boundaries of control. Providing empirical evidence for these boundaries is endorsed as an important goal for social scientific research.