<p>Although much research has focused on cognitive ability and the genetic and environmental factors that might influence it, this aspect of human nature is still far from being well understood. It has been well-established that certain factors such as age and education have significant impacts on performance on most cognitive tests, but the effects of variables such as cognitive pastimes and strategies used during testing have generally not been assessed. Additionally, no genetic variant has yet been unequivocally shown to influence the normal variation in cognitive ability of healthy individuals. Candidate gene studies of cognition have produced conflicting results that have not been replicable, and genome-wide association studies have not found common variants with large influences on this trait.</p><p>Here, we have recruited a large cohort of healthy volunteers (n=1,887) and administered a brief cognitive battery utilizing diverse, common, and well-known tests. In addition to providing standard demographic information, the subjects also filled out a questionnaire that was designed to assess novel factors such as whether they had seen the test before, in what cognitive pastimes they participated, and what strategies they had used during testing. Linear regression models were built to assess the effects of these variables on the test scores. I found that the addition of novel covariates to standard ones increased the percent of the variation in test score that was explained for all tests; for some tests, the increase was as high as 70%.</p><p>Next, I examined the effects of genetic variants on test scores. I first performed a genome-wide association study using the Illumina HumanHap 550 and 610 chips. These chips are designed to directly genotype or tag the vast majority of the common variants in the genome. Despite having 80% power to detect a common variant explaining at least 3-6% (depending on the test) of the variation in the trait, I did not find any genetic variants that were significantly associated after correction for multiple testing. This is in line with the general findings from GWA studies that single common variants have a limited impact on complex traits.</p><p>Because of the recent technological advances in next-generation sequencing and the apparently limited role of very common variants, many human geneticists are making a transition from genome-wide association study to whole-genome and whole-exome sequencing, which allow for the identification of rarer variants. Because these methods are currently costly, it is important to utilize study designs that have the best chance of finding causal variants in a small sample size. One such method is the extreme-trait design, where individuals from one or both ends of a trait distribution are sequenced and variants that are enriched in the group(s) are identified. Here, I have sequenced the exomes of 20 young individuals of European ethnicity: 10 that performed at the top of the distribution for the cognitive battery and 10 that performed at the bottom. I identified rare genetic variants that were enriched in one extreme group as compared to the other and performed follow-up genotyping of the best candidate variant that emerged from this analysis. Unfortunately, this variant was not found to be associated in a larger sample of individuals. This pilot study indicates that a larger sample size will be needed to identify variants enriched in cognition extremes.</p><p>Finally, I assessed the effect of topiramate, an antiepileptic drug that causes marked side effects in certain cognitive areas in certain individuals, on some of the healthy volunteers (n=158) by giving them a 100 mg dose and then administering the cognitive test two hours later. I compared their scores at this testing session to those at the previous session and calculated the overall level to which they were affected by topiramate. I found that the topiramate blood levels, which were highly dependent on weight and the time from dosing to testing, varied widely between individuals after this acute dose, and that this variation explained 35% of the variability in topiramate response. A genome-wide association study of the remaining variability in topiramate response did not identify a genome-wide significant association.</p><p>In sum, I studied the contributions of both environmental and genetic variables to cognitive ability and cognitive response to topiramate. I found that I could identify environmental variables explaining large proportions of the variation in these traits, but that I could not identify genetic variants that influenced the traits. My analysis of genetic variants was for the most part restricted to the very common ones found on genotyping chips, and this and other studies have generally found that single common genetic variants do not have large affects on complex traits. As we move forward into studies that involve the sequencing of whole exomes and genomes, genetic variants with large effects on these complex traits may finally be found.</p> / Dissertation

Plant-herbivore interactions are among the most common of ecological interactions. It is therefore not surprising that plants have evolved multiple mechanisms to defend themselves, using both constitutive chemical and physical barriers and by induced responses which are only expressed after herbivory has occurred. Herbivores, on the other hand, respond to these plant defenses by evolving counter-adaptations which makes defenses less effective or even useless. Adaptation can occur at different geographical scales, with varying coevolutionary interactions across a spatially heterogenous landscape. By looking at the underlying genes responsible for these defensive traits and herbivore related phenotypic traits, it is possible to investigate the coevolutionary history of these plant- herbivore interactions. Here I use molecular population genetic tools to investigate the evolutionary history of several inducible defense genes in European Aspen (Populus tremula) in Sweden. Two genes, belonging to the Polyphenol oxidase gene-family (PPO1 and PPO2), show skews in their site frequency spectrum together with patterns of diversity and divergence from an outgroup which correspond to signatures of adaptive evolution (Paper II). 71 single nucleotide polymorphisms (SNPs) from seven inducible defense genes (PPO1-PPO3, TI2-TI5) show elevated levels of population differentiation compared to control genes (genes not involved in plant defense), and 10 of these defense SNPs show strong signatures of natural selection (Paper III). These 71 defense SNPs also divides a sample of Swedish P. tremula trees into three distinct geographical groups, corresponding to a Southern, Central and Northern cluster, a patterns that is not present in control SNPs (Paper III). The same geographical pattern, with a distinct Northern cluster, is also observed in several phenotypic traits related to herbivory in our common garden in Sävar (Paper IV). These phenotypic traits show patterns of apparent local maladaptation of the herbivore community to the host population which could indicate the presence of “information coevolution” between plants and herbivores (Paper IV). 15 unique defense SNPs also show significant associations to eight phenotypic traits but the causal effects of these SNP associations may be confounded by the geographic structure found in both the underlying genes and in the phenotypic traits. The co-occurrence of population structure in both defense genes and herbivore community traits may be the result from historical events during the post-glacial recolonization of Sweden. / Interaktioner mellan växter och herbivorer är bland de vanligaste ekologiska interaktionerna och det är därför inte förvånande att växter har utvecklat flera olika mekanismer för att försvara sig. Dessa försvarsmekanismer består både av konstitutiva kemiska och fysiska barriärer så väl som inducerade försvar som bara är uttryckta efter att en växt har blivit skadad genom betning. Herbivorerna å sin sida svarar på dessa försvar genom att utveckla motanpassningar som gör växternas försvar mindre effektiva eller till och med verkningslösa. Dessa anpassningar kan ske över olika geografiska skalor beroende på om de samevolutionära interaktionerna varierar i ett rumsligt heterogent landskap. Genom att studera de underliggande gener som kontrollerar dessa försvarsegenskaper tillsammans med herbivorrelaterade fenotypiska egenskaper är det möjligt att undersöka den samevolutionära historien av interaktionerna mellan växter och herbivorer. Här använder jag mig av molekylärpopulationsgenetiska verktyg för att undersöka den evolutionära historien i flera inducerade försvarsgener hos asp (Populus tremula) i Sverige. Två gener, som tillhör genfamiljen Polyphenol-oxidaser (PPO1 och PPO2), uppvisar ett frekvensmönster som man förväntar sig vid positiv selektion. Detta mönster kan också ses i dessa geners diversitet samt i divergens från en utgrupp (Uppsats II). 71 ”single nucleotide polymorphisms” (SNPar) från 7 inducerade försvarsgener (PPO1-PPO3, TI2-TI5) visar förhöjda nivåer av populationsdifferentiering jämfört med kontrollgener (gener som inte är involverade i trädens försvar), och 10 av dessa försvars-SNPar visar även tecken på naturlig selektion (Uppsats III). Dessa 71 försvars-SNPar delar in ett urval av svenska aspar i tre distinkta geografiska grupper som beskriver ett sydligt, centralt och nordligt kluster som inte förekommer hos kontroll-SNPar (Uppsats III). Samma geografiska mönster, med ett distinkt nordligt kluster, återfinns däremot i ett antal fenotypiska egenskaper som är relaterade till herbivori i ett odlingsförsök utanför Sävar (Uppsats IV). Dessa fenotypiska egenskaper visar tecken på lokal felanpassning hos herbivorsamhället till den lokala värdpopulationen, vilket kan indikera förekomsten av ett ”samevolutionärt informationsutbyte” mellan växter och herbivorer (Uppsats IV). 15 unika försvars-SNPar påvisar också signifikanta associationer med 8 olika fenotypiska egenskaper, men om dessa har en verklig effekt eller inte är svårt att säga på grund av den geografiska strukturen som förekommer både hos de underliggande generna och hos de fenotypiska egenskaperna. Att denna populationsstruktur förekommer hos både försvarsgener och egenskaper som är förknippade med herbivorsamhället kan däremot vara ett resultat av historiska händelser som skett under aspens post-glaciala återkolonisation av Sverige.

<p>Complex disorders are caused by multiple genetic, environmental, and lifestyle factors, and their interactions. Most human diseases are complex, including many psychiatric, autoimmune, neurodegenerative, and cardiovascular disorders. Understanding their genetic background is an essential step toward developing effective preventive and therapeutic interventions for these disorders. In this dissertation, we present an overview of state-of-the-art methodology that is used to help elucidate the genetic basis of complex diseases and apply these methods to understand the genetic background of different complex disorders. First, we carried out a GWAS for myasthenia gravis (MG), a rare autoimmune disorder, and detected a novel risk locus, AGRN, which encodes a protein, involved in neuromuscular junction activation. Additionally, we observed significant genetic correlation between MG and ADs, and variants with pleiotropic effects. Second, we explored the genetic and phenotypic relationships among 11 different autoimmune disorders (ADs), using GWAS results o to calculate polygenic risk scores (PRS) and performing a PRS- phenome-wide association study (PheWAS) analysis with 3,281 phenotypes available in the UK Biobank. We observed associations of ADs PRS with phenotypes in multiple categories, including lifestyle, biomarkers, mental and physical health. We also explored the shared genetic components among the ADs, through genetic correlation and cross-disorder meta-analysis approaches, where we</p> <p>identified pleiotropic variants among the correlated ADs. Finally, we performed a meta-analysis GWAS of Tourette Syndrome (TS) followed by post-GWAS analyses including biological annotation of the results, and association tests of TS PRS with brain volumes. We detected a novel locus, NR2F1, associated with TS, supported by eQTL and Hi-C data. TS PRS was significantly associated with right and left thalamus volumes and right putamen volume. Overall, our work demonstrates the power of GWAS and related methods to help disentangle the genetic basis of complex disease and provides important insights into the genetic basis of the specific disorders that are the focus of our studies.</p>

Inbreeding can have profound negative effects on individuals by reducing fertility and viability. In populations, inbreeding depression can reduce growth rates and increases extinction risk. The aims of this thesis are to investigate inbreeding depression in male guppies (Poecilia reticulata) and to study the evolution of mechanisms for inbreeding avoidance in females, using guppies from a feral population in Queensland, Australia. Male guppies are highly polymorphic in their sexual ornamentation, indeed they show one of the most extreme polymorphisms observed in nature. Female guppies exhibit complex mate choice based on preferences for ornamentation, as well as social context. I aim is to examine how these factors of inbreeding avoidance alter sexual selection. In male guppies I found strong inbreeding depression in male sperm numbers, which is amplified under semi-natural compared to laboratory conditions (Chapter 2). Moreover, inbreeding depression results in low fertility under sperm competition: an experiment using artificial insemination techniques reveals that highly inbred males are heavily disadvantaged in gaining paternity (Chapter 3). On population level, inbreeding depression is manifest in reduced growth rates, predominantly in the early stages of inbreeding (Chapter 4). Population growth at inbreeding coefficients f=0.375-0.59 did not seem to lead to inbreeding depression, whereas lower levels of inbreeding reduced population growth. Although the growth rates in inbred populations appear normal, severe inbreeding depression is uncovered after outbred immigrants are added. Specifically, male immigrants are most efficient in short-term genetic rescue, probably due to insemination of large numbers of females whereas females are limited in the number of eggs they can produce (Chapter 4). Male ornamental traits show significant inbreeding depression in semi-natural conditions only (Chapters 2 & 3). Inbreeding avoidance mechanisms seem to have evolved in females: they prefer courtship displays of non-inbred males (Chapter 2), unfamiliar males (Chapter 5) and males with rare patterns (Chapter 6). This preference might increase the mating success of immigrants, and may have evolved to facilitate the avoidance of inbreeding. Together with context-independent preferences for ornament combinations (Chapter 6), it also offers an explanation for the maintenance of polymorphism in this species.

Inbreeding can have profound negative effects on individuals by reducing fertility and viability. In populations, inbreeding depression can reduce growth rates and increases extinction risk. The aims of this thesis are to investigate inbreeding depression in male guppies (Poecilia reticulata) and to study the evolution of mechanisms for inbreeding avoidance in females, using guppies from a feral population in Queensland, Australia. Male guppies are highly polymorphic in their sexual ornamentation, indeed they show one of the most extreme polymorphisms observed in nature. Female guppies exhibit complex mate choice based on preferences for ornamentation, as well as social context. I aim is to examine how these factors of inbreeding avoidance alter sexual selection. In male guppies I found strong inbreeding depression in male sperm numbers, which is amplified under semi-natural compared to laboratory conditions (Chapter 2). Moreover, inbreeding depression results in low fertility under sperm competition: an experiment using artificial insemination techniques reveals that highly inbred males are heavily disadvantaged in gaining paternity (Chapter 3). On population level, inbreeding depression is manifest in reduced growth rates, predominantly in the early stages of inbreeding (Chapter 4). Population growth at inbreeding coefficients f=0.375-0.59 did not seem to lead to inbreeding depression, whereas lower levels of inbreeding reduced population growth. Although the growth rates in inbred populations appear normal, severe inbreeding depression is uncovered after outbred immigrants are added. Specifically, male immigrants are most efficient in short-term genetic rescue, probably due to insemination of large numbers of females whereas females are limited in the number of eggs they can produce (Chapter 4). Male ornamental traits show significant inbreeding depression in semi-natural conditions only (Chapters 2 & 3). Inbreeding avoidance mechanisms seem to have evolved in females: they prefer courtship displays of non-inbred males (Chapter 2), unfamiliar males (Chapter 5) and males with rare patterns (Chapter 6). This preference might increase the mating success of immigrants, and may have evolved to facilitate the avoidance of inbreeding. Together with context-independent preferences for ornament combinations (Chapter 6), it also offers an explanation for the maintenance of polymorphism in this species.

Genetic mapping contributes to the understanding of functional mechanisms that underlie the constitution of living organisms and their physiology. For example, genetic mapping can be used in conceiving new treatments of congenital or infectious diseases and in selecting plants and animals that have a higher and better production. The most common approaches of genetic mapping exploit the allelic segregation in a pedigree during only a few number of generations and, consequently, they do not have a sufficient resolution to allow an effective gene isolation and cloning. An alternative to these approaches is to study allelic associations along the history of a population. This requires accurate models of population demography, genetic inheritance and allelic associations. This thesis contributes to the modelling of allelic associations (linkage disequilibrium, LD) and to the assessment of the effects of selection and inbreeding. In a simulation framework, we fitted the multimarker-multiallelic LD with an exponential function characterised by two parameters: the distance (R) at which LD is independent of the genetic distance and the LD reached at this distance (residual LD, rs). As an application of this approach, the LD was estimated in five populations of pigs. We observed a long range LD (>10cM) that was explained by the random drift. Moreover, significantly increased LD was found in regions harbouring selected QTL (quantitative trait loci), suggesting an effect of selection. Fitting LD with the exponential model proposed in simulations indicated that mapping methods using LD (LDM) can achieve a resolution of ~3cM in the populations of pigs we have studied and can be powerful with a marker spacing of 5-10cM. As illustrated with these data from pigs, the model that we used to fit LD offers opportunities to characterise allelic association in populations, estimate the required marker density for genome-wide LD studies and determine the expected resolution of LDM. It is also shown that the proposed model can help overcoming the assumptions of asymptotic linkage equilibrium and independence between markers that are commonly made in LDM but are not always fulfilled.

Inbreeding can have profound negative effects on individuals by reducing fertility and viability. In populations, inbreeding depression can reduce growth rates and increases extinction risk. The aims of this thesis are to investigate inbreeding depression in male guppies (Poecilia reticulata) and to study the evolution of mechanisms for inbreeding avoidance in females, using guppies from a feral population in Queensland, Australia. Male guppies are highly polymorphic in their sexual ornamentation, indeed they show one of the most extreme polymorphisms observed in nature. Female guppies exhibit complex mate choice based on preferences for ornamentation, as well as social context. I aim is to examine how these factors of inbreeding avoidance alter sexual selection. In male guppies I found strong inbreeding depression in male sperm numbers, which is amplified under semi-natural compared to laboratory conditions (Chapter 2). Moreover, inbreeding depression results in low fertility under sperm competition: an experiment using artificial insemination techniques reveals that highly inbred males are heavily disadvantaged in gaining paternity (Chapter 3). On population level, inbreeding depression is manifest in reduced growth rates, predominantly in the early stages of inbreeding (Chapter 4). Population growth at inbreeding coefficients f=0.375-0.59 did not seem to lead to inbreeding depression, whereas lower levels of inbreeding reduced population growth. Although the growth rates in inbred populations appear normal, severe inbreeding depression is uncovered after outbred immigrants are added. Specifically, male immigrants are most efficient in short-term genetic rescue, probably due to insemination of large numbers of females whereas females are limited in the number of eggs they can produce (Chapter 4). Male ornamental traits show significant inbreeding depression in semi-natural conditions only (Chapters 2 & 3). Inbreeding avoidance mechanisms seem to have evolved in females: they prefer courtship displays of non-inbred males (Chapter 2), unfamiliar males (Chapter 5) and males with rare patterns (Chapter 6). This preference might increase the mating success of immigrants, and may have evolved to facilitate the avoidance of inbreeding. Together with context-independent preferences for ornament combinations (Chapter 6), it also offers an explanation for the maintenance of polymorphism in this species.

Inbreeding can have profound negative effects on individuals by reducing fertility and viability. In populations, inbreeding depression can reduce growth rates and increases extinction risk. The aims of this thesis are to investigate inbreeding depression in male guppies (Poecilia reticulata) and to study the evolution of mechanisms for inbreeding avoidance in females, using guppies from a feral population in Queensland, Australia. Male guppies are highly polymorphic in their sexual ornamentation, indeed they show one of the most extreme polymorphisms observed in nature. Female guppies exhibit complex mate choice based on preferences for ornamentation, as well as social context. I aim is to examine how these factors of inbreeding avoidance alter sexual selection. In male guppies I found strong inbreeding depression in male sperm numbers, which is amplified under semi-natural compared to laboratory conditions (Chapter 2). Moreover, inbreeding depression results in low fertility under sperm competition: an experiment using artificial insemination techniques reveals that highly inbred males are heavily disadvantaged in gaining paternity (Chapter 3). On population level, inbreeding depression is manifest in reduced growth rates, predominantly in the early stages of inbreeding (Chapter 4). Population growth at inbreeding coefficients f=0.375-0.59 did not seem to lead to inbreeding depression, whereas lower levels of inbreeding reduced population growth. Although the growth rates in inbred populations appear normal, severe inbreeding depression is uncovered after outbred immigrants are added. Specifically, male immigrants are most efficient in short-term genetic rescue, probably due to insemination of large numbers of females whereas females are limited in the number of eggs they can produce (Chapter 4). Male ornamental traits show significant inbreeding depression in semi-natural conditions only (Chapters 2 & 3). Inbreeding avoidance mechanisms seem to have evolved in females: they prefer courtship displays of non-inbred males (Chapter 2), unfamiliar males (Chapter 5) and males with rare patterns (Chapter 6). This preference might increase the mating success of immigrants, and may have evolved to facilitate the avoidance of inbreeding. Together with context-independent preferences for ornament combinations (Chapter 6), it also offers an explanation for the maintenance of polymorphism in this species.

Inbreeding can have profound negative effects on individuals by reducing fertility and viability. In populations, inbreeding depression can reduce growth rates and increases extinction risk. The aims of this thesis are to investigate inbreeding depression in male guppies (Poecilia reticulata) and to study the evolution of mechanisms for inbreeding avoidance in females, using guppies from a feral population in Queensland, Australia. Male guppies are highly polymorphic in their sexual ornamentation, indeed they show one of the most extreme polymorphisms observed in nature. Female guppies exhibit complex mate choice based on preferences for ornamentation, as well as social context. I aim is to examine how these factors of inbreeding avoidance alter sexual selection. In male guppies I found strong inbreeding depression in male sperm numbers, which is amplified under semi-natural compared to laboratory conditions (Chapter 2). Moreover, inbreeding depression results in low fertility under sperm competition: an experiment using artificial insemination techniques reveals that highly inbred males are heavily disadvantaged in gaining paternity (Chapter 3). On population level, inbreeding depression is manifest in reduced growth rates, predominantly in the early stages of inbreeding (Chapter 4). Population growth at inbreeding coefficients f=0.375-0.59 did not seem to lead to inbreeding depression, whereas lower levels of inbreeding reduced population growth. Although the growth rates in inbred populations appear normal, severe inbreeding depression is uncovered after outbred immigrants are added. Specifically, male immigrants are most efficient in short-term genetic rescue, probably due to insemination of large numbers of females whereas females are limited in the number of eggs they can produce (Chapter 4). Male ornamental traits show significant inbreeding depression in semi-natural conditions only (Chapters 2 & 3). Inbreeding avoidance mechanisms seem to have evolved in females: they prefer courtship displays of non-inbred males (Chapter 2), unfamiliar males (Chapter 5) and males with rare patterns (Chapter 6). This preference might increase the mating success of immigrants, and may have evolved to facilitate the avoidance of inbreeding. Together with context-independent preferences for ornament combinations (Chapter 6), it also offers an explanation for the maintenance of polymorphism in this species.

A complex trait is a trait or disease that is controlled by both genetic and environmental factors, along with their interactions. Trait architecture encompasses the genetic variants and environmental causes of variation in the trait or disease, their effects on the trait or disease and the mechanism by which these factors interact at molecular and organism levels. It is important to understand trait architecture both from a biological viewpoint and a health perspective. In this thesis, I laid emphasis on exploring the influence of familial environmental factors on complex trait architecture alongside the genetic components. I performed a variety of studies to explore the architecture of anthropometric and cardio-metabolic traits, such as height, body mass index, high density lipoprotein content of blood and blood pressure, using a cohort of 20,000 individuals of recent Scottish descent and their phenotype measurements, Single Nucleotide Polymorphism (SNP) data and genealogical information. I extended a method of variance component analysis that could simultaneously estimate SNP-associated heritability and total heritability whilst considering familial environmental effects shared among siblings, couples and nuclear family members. I found that most missing heritability could be explained by including closely related individuals in the analysis and accounting for these close relationships; and that, on top of genetics, couple and sibling environmental effects are additional significant contributors to the complex trait variation investigated. Subsequently, I accounted for couple and sibling environmental effects in Genome- Wide Association Study (GWAS) and prediction models. Results demonstrated that by adding additional couple and sibling information, both GWAS performance and prediction accuracy were boosted for most traits investigated, especially for traits related to obesity. Since couple environmental effects as modelled in my study might, in fact, reflect the combined effect of assortative mating and shared couple environment, I explored further the dissection of couple effects according to their origin. I extended assortative mating theory by deriving the expected resemblance between an individual and in-laws of his first-degree relatives. Using the expected resemblance derived, I developed a novel pedigree study which could jointly estimate the heritability and the degree of assortative mating. I have shown in this thesis that, for anthropometric and cardio-metabolic traits, environmental factors shared by siblings and couples seem to have important effects on trait variation and that appropriate modelling of such effects may improve the outcome of genetic analyses and our understanding of the causes of trait variation. My thesis also points out that future studies on exploring trait architecture should not be limited to genetics because environment, as well as mate choice, might be a major contributor to trait variation, although trait architecture varies from trait to trait.