DNA methylation (DNAm) is the covalent modification of DNA by addition of a methyl group primarily at the cytosine directly upstream of a guanine. DNAm level plays a central role in transcriptional regulation and is linked to disease. Therefore, understanding genetic and environmental influences on DNAm level in healthy tissue is an important step in the elucidation of trait and disease etiology. However, at present only a minority of easy to access human tissues and ethnicities have been investigated. Therefore, we studied DNAm level measured in five human tissues: cerebellum, frontal cortex, pons, temporal cortex and colon in either North American or South American samples. We applied a novel statistical approach to estimate the heritability attributable to genomic regions (regional heritability, ĥ²/r,g ) for DNAm level at thousands of individual DNAm sites genome-wide. In all five tissues, DNAm level was significantly associated with the local genomic region for more DNAm sites than expected by chance. Moreover, DNAm level could be predicted from the local sequence variants with an accuracy that scaled with the estimated ĥ²/r,g . Our results inform on molecular mechanisms regulating DNAm level and trait etiology in several ways. Firstly, DNAm level at DNAm sites located in genomic risk regions and measured in a tissue relevant to the disease can be influenced by the local genetic variants. Specifically, we found that genetic variation within a region associated with Fluid Intelligence was also associated with local DNAm level at the proline-rich coiled-coil 1 (PRRC1) gene in healthy temporal cortex tissue. Additionally, we replicated the finding of a Colorectal Cancer risk variant (rs4925386) associated with two DNAm sites in healthy colon tissue. More generally, we showed that DNAm sites located within a susceptibility region and measured in a relevant tissue exhibit a similar overall pattern of estimated ĥ²/r,g to DNAm sites outwith a susceptibility region. Secondly, the propensity for DNAm level to be associated with the local sequence variation differs with respect to CpG dinucleotide density and genic location. Most notably, DNAm sites located in CpG dense regions of the genome are less likely to be heritable than DNAm sites located in CpG sparse regions of the genome. Additionally, within both CpG dense and CpG sparse regions of the genome intergenic DNAm sites are more likely to be heritable than intragenic DNAm sites. Overall, our study suggests that variation in DNAm level at some DNAm sites is at least partially controlled by nuclear genetic variation. Moreover, DNAm level in healthy tissue has the potential to act as an intermediary in trait variation and etiology.

Most human traits are influenced by a combination of genetic and environmental effects. Heritability expresses the proportion of trait variance that can be explained by genetic factors, and the 1980s heralded the beginning of studies that aimed to pinpoint genetic loci that contribute to trait variation, also known as quantitative trait loci (QTLs). Subsequently, the availability of cheap, high-resolution genotyping chips ushered in the era of genome-wide association studies (GWAS). These genetic studies have discovered many associations between single-nucleotide polymorphisms (SNPs) and complex traits, but these associations do not explain the genetic component of these traits entirely. This is known as the ‘missing heritability’ problem. Within this thesis, 40 medically-relevant human complex traits are studied in order to identify new QTLs. These traits include eye biometric traits, blood biochemical traits and anthropometric traits measured in approximately 28,000 individuals belonging to family-based samples from the general Scottish population (the Generation Scotland study) or from population isolates from Croatian (Korčula, Vis) or Scottish (Shetland, Orkney) islands. These individuals had been genotyped using commercially-available arrays, and unobserved genotypes were imputed using the Haplotype Reference Consortium (HRC) dataset. In parallel to standard GWAS, these traits are analysed using two other statistical genetics approaches: variance component linkage analysis and regional heritability (RH) mapping. Each study is analysed separately, in order to detect study-specific genetic effects that may not generalise across populations. At the same time, because most traits are available in several studies, this also enables meta-analysis, which boosts the power of discovery and can reveal cross-study genetic effects. These methods are a priori complementary to each other, exploiting different aspects of human genetic variation, such as the segregation of variants within families (identity by descent, IBD), or the presence of the same variant throughout the general population (identity by state, IBS). The strengths and weaknesses of these methods are systematically assessed by applying them to real and simulated datasets.

Made available in DSpace on 2014-06-11T19:22:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-10Bitstream added on 2014-06-13T19:49:06Z : No. of bitstreams: 1 barbieri_ra_me_rcla.pdf: 863448 bytes, checksum: 43a26fd5f52aa3934b593e170d424fb1 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Baixa atividade física e aptidão cardiorrespiratória estão associadas diretamente a resistência a insulina que pode ser considerada como fator inicial para posteriores distúrbios, como aumento da adiposidade corporal, hipertensão, intolerância a glicose e dos teores de lipídios no sangue. Apesar destas anormalidades possuírem um componente herdado significativo, pouco se conhece sobre a relação entre as influências genéticas e ambientais para estas variáveis na população brasileira, muito menos em crianças e adolescentes. Portanto, o objetivo do presente estudo foi estabelecer a contribuição de fatores genéticos e ambientais na variância da aptidão cardiorrespiratória, atividade física e metabolismo de glicose em crianças e adolescentes gêmeos. Para realização do estudo gêmeos do mesmo sexo entre 11 e 18 anos matriculados em 19 escolas publicas e 5 particulares do município de Rio Claro- SP (6º ao 3º ano do ensino médio) foram cadastrados e convidados a participar. Aqueles que concordarem foram submetidos a medidas de pedometria para estimativa da AF diária, a um teste de esforço para determinação da capacidade aeróbia e a uma coleta de sangue periférico a fim de determinar a concentração de glicose e insulina, além de uma bateria de medidas antropométricas. A partir de um questionário aplicado aos pais e aos gêmeos, os pares foram classificados em monozigóticos (idênticos) e dizigóticos (fraternos). Para o tratamento estatístico inicialmente foi utilizada a estatística descritiva para agrupar os resultados, a análise de variância para estimar a similaridade dentro dos pares de gêmeos calculando a herdabilidade através da equação h2 = 2(rMZ - rDZ). Os resultados obtidos mostraram que as medidas antropométricas possuem um forte componente genético, principalmente para os meninos (40% a 100%), porém com moderado impacto do ambiente... / Low physical activity and cardiorespiratory fitness are associated directly with the insulin resistance that can be considered as initial factor for later disorders, such as increased adiposity, hypertension, impaired glucose tolerance and lipids in the blood. Despite these abnormalities have a significant inherited component, little is known about the relationship between genetic and environmental influences for these variables in our population, much less in children and adolescents. Therefore, the aim of this study was to establish the contribution of genetic and environmental variance in cardiorespiratory fitness, physical activity and glucose metabolism in children and adolescent twins. For the study of same-sex twins between 11 and 18 years enrolled in 19 public and 5 private schools in the municipality of Rio Claro-SP (6º to 3º year of high school) were registered and invited to participate. Those who agree underwent pedometrics measures to estimate daily AF, effort test to determine aerobic capacity and a collection of peripheral blood to determine the concentration of glucose and insulin, plus a battery of anthropometric measurements. From a questionnaire administered to parents and twins, the couple were classified as monozygotic (identical) and dizygotic (fraternal). The statistic was first used descriptive statistics to group the results, analysis of variance to estimate the similarity within pairs of twins calculated the heritability of the equation h2 = 2(rMZ - rDZ). The results showed that the anthropometric measures have a strong genetic component, especially for boys (40% to 100%), but with a moderate impact on the environment for girls (34% to 80%). Already AF weekly usual cardiorespiratory fitness and suffer a moderate impact of genetics for the boys (6% to 72%) and girls receiving a large influence of the environment (45% to 100%). The metabolism of glucose... (Complete abstract click electronic access below)

Genomic prediction (GP) is a novel tool used for prediction of EBVs by using molecular markers. Within the last decade, GP has been widely introduced into routine evaluations of cattle, pig and sheep populations, however, its application in poultry has been somewhat delayed, and studies published to date have been limited in terms of population size and marker densities. This study shows a thorough evaluation of the benefits that GP could bring into routine evaluations of broiler chickens, with particular attention given to the accuracy and bias of Genomic BLUP (GBLUP) predictions. The data used for these evaluations exceeds the numbers of both individuals and marker genotypes of previously published reports, with the studied population consisting of up to 23,500 individuals, genotyped for up to 600K SNPs. The evaluation of GBLUP is preceded by evaluation of the variance components using traditional restricted maximum likelihood (REML) approach sourcing information from phenotypic records and pedigree, which provide an up to date reference for the estimates of variance components. Chapter 2 tested several models exploring potential sources of genetic variation and revealed the presence of significant maternal genetic and environmental effects affecting several commercial traits. In Chapter 3, a vast dataset containing 1.3M birds spread over 24 generations was used to evaluate changes in genetic variance of juvenile body weight and hen housed production over time. The results showed a slow but steady decline of the variance. Chapter 4 provided initial estimates of the accuracy and bias of genomic predictions for several sex-limited and fitness traits, obtained for a moderately sized population of over 5K birds, genotyped with 600K Affymetrix Axiom panel from which several chips of varying marker densities were extracted. The accuracy of those predictions showed a great potential for most traits, with GBLUP performance exceeding that of traditional BLUP. Chapter 5 investigated the effect of marker choice, with two chips used: one created from GWAS hits and second from evenly spaced markers, both with constant density of 27K SNPs. The two chips were used to calculate genomic relationship matrices using Linkage Analysis and Linkage Disequilibrium approaches. Markers selected through GWAS performed better in Linkage Analysis than in Linkage Disequilibrium approach. The optimum results however were found for relationship matrices which regressed the genomic relationships back to expected pedigree-based relationships, with the best regression coefficient dependent on the chip used. Chapter 6 formed a comprehensive evaluation of the utility of GBLUP in a large broiler population, exceeding 23,500 birds genotyped using 600K Affymetrix Axiom panel. By splitting the data into variable scenarios of training and testing populations, with several lower density chips extracted from the full range of genotypes available, the effect of population size and marker density was evaluated. While the latter proved to have little effect once 20K SNPs threshold was exceeded, the effect of the population size was found to be the major limiting factor for the accuracy of EBV predictions. The discrepancy between empirical results found and theoretical expectations of accuracy based on the similar genomic and population parameters showed an underestimation of the previously proposed requirements.

The objectives of this dissertation were to evaluate genetic and environmental relationships between lamb and ewe traits including body weight, fleece weight and quality, prolificacy, body condition, ewe stayability and lamb survival. Average heritability estimates for lamb birth weight (BWT), weaning weight (WW), maternal weaning weight, yearling body weight, fleece weight, spinning count and staple length were 0.19, 0.09, 0.08, 0.35, 0.38, 0.25, and 0.31 respectively. Heritability estimates for adult traits averaged 0.43 for body weight (AW), 0.13 for body condition (AC), and 0.12 for number of lambs born per ewe lambing (NLB). Correlations between direct additive AW and direct additive and maternal lamb weights ranged from 0.21 to 0.96 (P < 0.05) and 0.29 to 0.53 (P < 0.05), respectively, with residual correlations ranging from 0.05 to 0.95. Correlations of lamb traits with adult body condition and NLB were generally not different from zero; genetic and residual correlations ranged from -0.52 to 0.69 and -.39 to 0.31, respectively. Ewe stayability was analyzed as overall stayability (STAYn|2) which indicated the presence or absence of a ewe at n yrs of age, given that she was present at 2 yrs of age, and marginal stayability (STAYn|1-n) recording the presences of a ewe at n yrs of age, given that she was in the flock the previous year. Additive variance in ewe stayability was only found in stayability at 5 and 6 yr of age (P < 0.05). Heritability estimates for STAY5|4 and STAY6|2 from multiple trait analyses with other traits averaged 0.08 and 0.10, respectively. Phenotypic correlations between STAY and all other traits were near zero, ranging from -0.04 to 0.03. The estimated correlations between additive effects on STAY5|4 and STAY6|2 and additive maternal effects on WW were positive (both 0.46; P < 0.05). Genetic correlations between STAY5|4 and WW, adult weight, and NLB were 0.06, 0.13 and -0.06 (P > 0.10), respectively. However, genetic correlations between STAY6|2 and WW, adult weight, and NLB were negative (-0.17, -0.32 (P < 0.05) and -0.03, respectively). Significant genetic variation was thus present in stayability, with nonzero genetic correlations present between STAY, maternal milk, WW, and adult weight. Survival analysis was performed using a proportional hazards model to measure the probability of lamb death before weaning. Lamb survival was recorded as the day of age at death. Records were censored if a live lamb was artificially removed from their litter before death. Fixed effects on survival included ewe age, litter size, sex, and linear and quadratic BWT. Average age of death was 13.7 d. Censoring of records before weaning occurred in 12.9% of the total lambs born. Risk ratios indicated lambs from yearlings and ewes older than 5 yr had the greater risk of death, as did triplet and quadruplet lambs. Linear and quadratic BWT effects on lamb survival were found (P < 0.05) and accounted for most of the litter size effects in large litters. The influence of informative censoring was considered by assuming that lambs censored by 3 d of age had died at the time of censoring. Heritability of lamb survival at 3 d of age (estimated using an animal model in MTDFREML) was near zero, ranging from 0.00 to 0.01. The lack of additive variance suggests that improvement in lamb survival should be made through changes in management practices. / Ph. D.

Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. © 2021 Society of Biological Psychiatry / National Institutes of Health / Revisión por pares

BACKGROUND: Growth of the cranial base and its structures are of particular interest to the orthodontic community. The midface and nasal bones have a significant influence on facial esthetics and thus pattern recognition of facial growth from parental data can influence orthodontic treatment plans. We aimed to determine if there is a similarity in midface and nasal bone and soft tissue growth between a child and either parent. MATERIALS AND METHODS: This cross-sectional study was comprised of forty-seven western European families from the Forsyth/Moorrees Twin Study. The lateral cephalograms of each parent and post pubertal child, who were at least 2 years past peak growth (age ≥ 16 yrs for females and ≥ 17 yrs for males) were evaluated on fourteen cephalometric variables. The radiographs were digitized and analyzed using the Mimics™ software program (Materialise, Leuven, Belgium) by a single investigator. A linear regression analysis was used to correlate linear and angular measurements to one another. An ANOVA with multiple comparisons (TUKEY) was performed to test for the differences between family members controlling for the effect of the individual family (as each family has a trend within itself). Age and gender interactions were tested for in the models. Statistical significance was set at p < 0.05. RESULTS: Twenty-five male and twenty-two female children and their parents were studied. When comparing the fourteen parameters between the mean of the child and both parents, a significant difference (p < 0.05) was found between the child and the father but not the mother in six measurements. These included the ratio of nasal height to total face height, angle of nasal bone to SN, distance from rhinion to pronasale (mm), distance from ANS to pronasale (mm), projection of nose (mm) and nasal length (mm). A significant difference was also found between the child and the mother, but not the father for rhinion to ANS (mm). A significant difference was found between the child and both parents for nasal height (mm). When controlling for family and isolating the gender of the child, males and females were not significantly different from their fathers for ratio of nasal height to total face height. For angle of nasal bone (S-N-Rh) and nasal length (N’-vertical line from Pro), females but not males were significantly different from the father. Both girls and boys were still significantly different from the father in the rhinion to pronasale and ANS to pronasale distances, projection of nose and nasal heights. Only males showed a significant difference from the mother for rhinion to ANS and nasal height when isolated for by gender. CONCLUSION: Statistically significant differences were found between the child and father and not the mother for six out of our fourteen measurements of interest. Two measurements of interest showed a difference between the child and the mother and not the father and one showed a significant difference from both parents. From this study we conclude that children tend to be morphologically less similar to their fathers when comparing midface and nasal soft and hard tissue parameters.

The similarities between generations of living subjects are often quantified by heritability. By distinguishing genotypic variation, or variation due to parental pairings, from phenotypic variation, or normal intraspecies variation, the heritability of traits can be estimated. Due to the multivariate nature of many traits, such as size and shape, computation of heritability can be difficult. Also, assessment of the variation of the heritability estimate is extremely difficult. This study uses nonparametric methods, namely the randomization test and the bootstrap, to obtain both a measure of the extremity of the observed heritability and an assessment of the uncertainty.

Circadian rhythms are nearly ubiquitous and are responsible for timing biological processes and allowing for anticipation of regular changes in the environment. The internal clocks of most organisms have a period very close to 24 hours with little variation. Spiders, however, do not seem to follow this pattern. Both the fastest (18 hours) and slowest (29 hours) naturally-occurring clocks are found in spiders, and variation within a species can be orders of magnitude larger than that of previously studied animals. Circadian rhythms are assumed to be adaptive, yet little is known about their heritability in arthropods. Heritability is defined as the amount of phenotypic variation that can be attributed to genetic variation passed down from parent to offspring. Phenotype can be influenced by many complex factors including environmental effects, dominance of genetic sequences, and gene interactions. Because of these influences, the phenotypic characteristics of an individual can vary greatly, and it is often difficult to precisely identify what is truly heritable. Using spiders as a model system, we can exploit the extreme variation in circadian rhythms to investigate the potential contribution from heritability. Strong heritability would suggest that wide variation in circadian rhythms likely reflects high genetic variability in the species. Alternatively, the environment may have a greater contribution in this variation relative to the effects of heritability. To test this, we chose Parasteatoda tepidariorum, a common cobweb spider with a relatively short circadian period of 21.7 hours and intraspecific variation of more than 4 hours. To estimate the heritability of circadian rhythm, adult females were gathered with accompanying egg cases, and juveniles were raised from those cases. Six fundamental parameters of circadian rhythms were measured from the locomotor activity of adults and juveniles. Of those six, only one parameter differed between adults and juveniles: the onset of locomotor activity during the first five days when light cycles were present (Mann-Whitney U= 1814, p= 0.04). When all six circadian parameters were compared by regression of adults to respective offspring, none showed significant correlation. This indicates that variation in circadian rhythms was likely not caused by parental genetics, and that environmental factors, such as artificial light at night, may be the source of the extreme circadian rhythms seen in spiders. Another possible cause for this variation may be the presence of weak molecular circadian oscillators that are more sensitive to environmental factors than those in most other circadian systems.

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