Parental influences on cardiovascular disease (CVD) risk in children can be linked to their own earlier nutritional or socio-economic circumstances. We examined the association of parental height, a sensitive proxy marker of early life circumstances, with offspring cardiovascular disease risk in the Andhra Pradesh Children and Parents Study (APCAPS) in Southern India. We present data from subjects in 1129 households (N=4369) in 20 study villages where we examined the association of parental height (Mothers N=987, Fathers N=798) with CVD risk factors in children (N=2581, mean age=22.3yrs, Males=58.9%) using multiple regression analyses, adjusting for potential confounders and accounting for family-level clustering. Maternal and paternal height were positively associated with offspring height [β =0.302(0.274, 0.331) and 0.271(0.239, 0.302)], weight [β= 0.170(0.137, 0.203) and 0.167(0.128, 0.205)],body mass index[β=0.034(-0.003,O.070) and 0.042(- 0.001,0.0084)], waist [P=0.066(0.033,O.099) and 0.068(0.033,O.105)]and hip[β=0.140(0.105,O.176) and 0.152(0.109,O.194)]circumferences, total body fat [β =0.102(0.062,0.142) and 0.082(0.043,O.122)]and fat-free mass[β=0.152(0.122,O.181) and 0.173(0.140,0.206)]. Most of these effects were attenuated or lost on accounting for child's current socio-economic status and height. Maternal height showed a positive association, robust to adjustment, with HOMA and diastolic blood pressure only among female offspring, while paternal height was positively associated with offspring LDL-C and inversely with systolic and diastolic blood pressure. There was no association with other biochemical and vascular outcomes. Comparison of maternal versus paternal height influences showed differences for offspring fasting insulin, HOMA insulin resistance and diastolic blood pressure. Taller maternal height leading to improved offspring birth outcomes and later cardiovascular risk has been shown in Western populations. In our study, increasing parental height was associated with increases, rather than decreases in most offspring CVD risk factors, after accounting for potential confounders and mediators. This points to the potential role of lifestyle factors such as unhealthy diet and physical inactivity associated with increased urbanization as putative causative factors in this phenomenon.

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Genetic variation in the gene ZNF804A has been shown to be related to risk for psychopathology, especially schizophrenia and bipolar disorder. The main aim of this thesis was to characterise the behavioural effects of Zfp804a, the mouse orthologue of ZNF804A, in order to understand more about how this gene influences brain and psychological functioning, and hence provide clues as to its possible role in mediating risk for mental disorders. Prior to this work, two ENU-mutant mouse lines had been generated from a DNA library of ENU mutagenised mice with two non-synonymous mutations selected as viable candidates for further investigation. The C59X mutation encodes a premature stop codon in exon 2, thought to lead to a functional null of the gene, and the C417Y mutation is missense, substituting cysteine for tyrosine in exon 4. A first series of experiments examined the early development of the ENU-mutant lines and showed no gross developmental abnormalities, although the C59X mutants weighed significantly less than their WT littermate controls at weaning and during adulthood. A comprehensive series of behavioural tests then assayed aspects of emotion, motivation, hedonia, sensorimotor gating and response control. In general, the C59X mutants showed the greatest effects, displaying reduced anxiety, anhedonia, and sensorimotor gating deficits, together with evidence of enhanced response inhibition. The C417Y mutants only showed selective effects in terms of enhanced motivation. The data dissociate between the effects of the two ENU-induced mutations of Zfp804a. Furthermore, the findings with the C59X mutants would suggest, a priori, that genetic variance leading to alterations in ZNF804A expression may be an important mechanism contributing to risk for psychopathology.

Les populations humaines ont été confrontées à de nombreux changements environnementaux au cours de leur histoire et présentent aujourd’hui une grande diversité d’habitats et de modes de subsistance. Cependant, l’ampleur de l’adaptation génétique et des réponses épigénétiques à ces changements est débattue. Nous avons d’abord étudié la puissance de diverses statistiques pour détecter les balayages sélectifs dans le contexte des données de séquençage à haut débit, et évalué leur robustesse à différents facteurs confondants. En utilisant des jeux de données de séquençage, nous montrons que les balayages sélectifs ont eu un impact modéré mais non négligeable dans l’évolution récente du génome humain. Les régions sous sélection sont enrichies en mutations associées à des variations phénotypiques. Nous avons ensuite évalué l’impact respectif des facteurs génétiques et environnementaux sur la diversité épigénétique humaine. Pour cela, nous avons obtenu les génotypes et les profiles de méthylation de l’ADN de populations d’Afrique Centrale présentant des différences récentes d’habitat ou historiques de modes de vie et de profil génétique. Nous montrons que les deux facteurs ont un effet similaire sur le méthylome mais diffèrent par les fonctions biologiques affectées et les mécanismes expliquant les variations observées. Plus généralement, les variations de méthylation sont fortement associées à des mutations génétiques qui sont enrichies en signaux de sélection positive. En conclusion, ce travail apporte un aperçu de la contribution des mutations génétiques et des réponses épigénétiques à l’adaptation humaine aux changements environnementaux sur plusieurs échelles de temps. / Human populations have faced a large number of environmental challenges during their evolutionary history and present today a wide range of habitats and mode of subsistence. However, the extent of genetic adaptation and epigenetic responses to such environmental variation remains controversial. We first explored the power of several statistics to detect hard selective sweeps in the context of whole-genome sequencing data, and evaluated their robustness to demography and other selection modes. Using data from the 1,000 Genomes Project and Complete Genomics, we showed that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution. The signals of selection detected were moreover enriched in functional variants detected by genome-wide association studies. We then evaluated the relative impacts of genetic and environmental factors on human epigenomic diversity. To do so, we generated genome-wide genetic and DNA methylation profiles for Central African populations differing in their current habitat or in their historical lifestyle and genetic background. We found that both factors have similar critical impacts on the shaping of the global methylome, but the biological functions affected and the mechanisms underlying DNA methylation variation strongly differ. More generally, methylation variation shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Together, this work provides new insight into the contribution of genetic adaptation and epigenetic responses to the adaptation of humans to environmental changes over different time scales.