Relative Genetic Contributions Research Articles

Testing the Deliberate Practice Theory: Does Practice Reduce the Heritability of Musical Expertise?

The deliberate practice (DP) theory claims that expertise essentially reflects the accumulated amount of deliberate practice, and that with sufficient practice, genetic influences on expertise will be bypassed. Thus, a core prediction of the DP theory is that genetic effects on performance decrease as a function of practice. Here, we test this prediction using music as a model domain. Musical expertise (measured with a musical auditory discrimination test) and lifetime practice hours were determined in 6471 twins including 1302 complete twin pairs. We fitted a bivariate Cholesky decomposition with practice hours as a moderator to determine to what extent genetic and environmental influences on musical expertise are influenced by practice hours. On average, 50% of individual differences in musical expertise were due to genetic influences, whereas shared environmental and residual influences each explained about 25%. Importantly, music practice significantly moderated these estimates. Variation in musical expertise decreased with more practice hours due to decreased shared environmental and residual variance. In contrast, the overall genetic component was unaffected by the number of practice hours. Consequently, the relative genetic contribution (heritability) increased with more practice hours. These findings are in contrast with predictions from the DP theory and suggest that genetic predisposition remains important for musical expertise even after prolonged practice.

Linking the spatial and genomic structure of adaptive potential for conservation management: a review.

We unified the recent literature with the goal to contribute to the discussion on how genetic diversity might best be conserved. We argue that this decision will be guided by how genomic variation is distributed among manageable populations (i.e. its spatial structure), the degree to which adaptive potential is best predicted by variation across the entire genome or the subset of that variation that is identified as putatively adaptive (i.e. its genomic structure), and whether we are managing species as single entities or as collections of diversifying lineages. The distribution of genetic variation and our ultimate goal will have practical implications for on-the-ground management. If adaptive variation is largely polygenic or responsive to change, its spatial structure might be broadly governed by the forces determining genome-wide variation (linked selection, drift, and gene flow), making measurement and prioritization straightforward. If we are managing species as single entities, then population-level prioritization schemes are possible so as to maximize future pooled genetic variation. We outline one such scheme based on the popular Shapley Value from cooperative game theory that considers the relative genetic contribution of a population to an unknown future collection of populations.

Genetic and environmental interactions contribute to immune variation in rewilded mice

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease.

Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types such as macrophages. We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis-the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo. We identified 18 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-β in the causal mechanisms at this locus. Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

The Etiology of Parkinson's Disease: New Perspectives from Gene-Environment Interactions.

Parkinson's disease is now the most rapidly growing neurodegenerative disease worldwide. It is therefore critical to identify which factors, and to what extent, contribute to the multifactorial etiology of Parkinson's disease. Here, we address two interesting elements from the perspective of genetics, namely (a) the estimated age of several genetic risk factors related to Parkinson's disease; and (b) the relative contribution of genetics to the etiology of Parkinson's disease, as derived from twin studies. Based on these two perspectives, we argue that most genetic risk factors are by themselves insufficient to explain the majority of Parkinson's disease, and that environmental factors are required for these genetic factors to become pathophysiologically relevant.

The contribution of genetics to dental caries, oral habits and occlusal traits in Turkish twins: A comparative study

ObjectiveThe aims of this study were to investigate and compare the prevalence of dental caries and the frequency of oral habits, molar relationships and occlusal traits between children of multiple births, and singletons, and to determine the relative contributions of genetics and environmental factors to these parameters by using twin study design.MethodsThe study group consisted of 345 multiple births (34 monozygotic and 122 dizygotic twin pairs, 11 sets of triplets) and 345 singletons between the ages of 2 and 17. The prevalence of dental caries, and the frequency of tooth brushing, the children’s oral habits, molar relationships, and occlusal traits were recorded.ResultsThe percentage of children who brushed their teeth more than twice daily was statistically significantly higher in multiple births than in singletons. Higher correlation coefficients were found in dental caries index, except for decayed, filled (df) (2–5 age group) and filled (f) (6–11 age group), in the monozygotic twin pairs compared to those in the dizygotic twin pairs. In children between the ages of 6 and 11 years, mouth breathing, bruxism, lip biting, and pencil biting were higher in singletons than in children of multiple births. There were statistically significant differences between children of multiple births and singletons, with increased overjet in the 2–5 year age group being observed.ConclusionWhen analyzing these parameters, environmental factors must also be investigated. Due to the low incidence of twin births, longitudinal follow-up studies with more twin pairs are necessary to determine whether these results are generalizable.

Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins

Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins’ models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.This article is part of the Special Issue on “Microbiome & the Brain: Mechanisms & Maladies”.

Sperm mobility is predictive of the relative genetic contribution among competing mating geese, as determined by microsatellite genotype identification of potential sires

The low reproductive efficiency (RE) of geese limits their production in the poultry industry. To select ganders with high breeding potential, the effect of 3 sperm mobility ranks (SMRs; high-, medium-, and low-SMR) on the RE of naturally mating geese was determined. To exclude the confounding effect of social rank (SR) on RE in naturally mating flocks, a 2-factor nested experimental design was used to differentiate the effects of SMR and SR on RE. Twenty-seven ganders and 135 geese (Zi geese, Anser cygnoides L.) at approximately 1 yr of age were divided into 3 flocks, each of which included the 3 SMR groups. Each SMR group included 3 ganders and 15 female geese. Relative genetic contribution (RGC) is defined as the number of offspring sired by 1 male as a percentage of the entire goslings in each flock, and it was used to compare the differences in RE among ganders. The frequency of agonistic behavioral interactions (ABIs) among the ganders was video recorded in each SMR group, and the SR of each gander was determined. In total, 1,026 eggs were incubated, and 609 goslings hatched. Parent-offspring relationships among 771 individuals from the 2 generations were identified using 20 microsatellite markers, and the RGC was calculated. Results showed that the SMR and SR had significant effects on RGC in naturally mating geese (P=0.001 and P=0.000, respectively). Significant differences in RGC were observed among the high- and medium- and low-SMR groups, with average RGCs of 14.3, 10.6, and 8.4%, respectively. The high-SMR group had the highest RGCs in each flock, and the ganders with high SR had the highest RGCs among the 3 SMRs. The study showed that in a naturally mating geese population, selecting for the sperm mobility traits of a gander can effectively improve the RE.

Different proxies, different stories? Imperfect correlations and different determinants of fitness in bighorn sheep.

Measuring individual fitness empirically is required to assess selective pressures and predicts evolutionary changes in nature. There is, however, little consensus on how fitness should be empirically estimated. As fitness proxies vary in their underlying assumptions, their relative sensitivity to individual, environmental, and demographic factors may also vary. Here, using a long-term study, we aimed at identifying the determinants of individual fitness in bighorn sheep (Ovis canadensis) using seven fitness proxies. Specifically, we compared four-lifetime fitness proxies: lifetime breeding success, lifetime reproductive success, individual growth rate, individual contribution to population growth, and three multi-generational proxies: number of granddaughters, individual descendance in the next generation, and relative genetic contribution to the next generation. We found that all proxies were positively correlated, but the magnitude of the correlations varied substantially. Longevity was the main determinant of most fitness proxies. Individual fitness calculated over more than one generation was also affected by population density and growth rate. Because they are affected by contrasting factors, our study suggests that different fitness proxies should not be used interchangeably as they may convey different information about selective pressures and lead to divergent evolutionary predictions. Uncovering the mechanisms underlying variation in individual fitness and improving our ability to predict evolutionary change might require the use of several, rather than one, the proxy of individual fitness.

Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Age is the primary risk factor for many common human diseases. Here, we quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues from 948 humans. We show that the predictive power of expression quantitative trait loci is impacted by age in many tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find expression heritability (h2) is consistent among tissues while the contribution of aging varies by >20-fold with {R}_{{{{{{{{rm{age}}}}}}}}}^{2} ; > ;{h}^{2} in 5 tissues. We find that while the force of purifying selection is stronger on genes expressed early versus late in life (Medawar’s hypothesis), several highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression-associated somatic mutations. In contrast, genes under genetic control are under relaxed constraint. Together, we demonstrate the distinct roles of aging and genetics on expression phenotypes.

Patterns of phenotypic plasticity along a thermal gradient differ by trait type in an alpine plant

Abstract Climate change presents many challenges for plants, a major one of which is the steady increase in the temperatures that plants are exposed to during germination, growth and reproduction. Generating a more complete understanding of the capacity for plants to respond and of the role that phenotypic plasticity plays in facilitating species' responses to warming temperatures is a central objective in global change ecology. Different traits expressed across life stages might be expected to exhibit a variety of responses to temperature due to phenotypic plasticity and genetic variation, even within a species. However, the extent of the variation among trait types and the relative contribution of plasticity and genetics to responses along a thermal gradient are not well understood. Here, we studied an alpine plant, Wahlenbergia ceracea, to determine the shapes of plastic responses in 14 traits across germination, leaf, physiology and reproductive fitness trait types across a broad thermal gradient of temperatures while also comparing responses among family lines. Trait types differed markedly: germination, leaf and reproductive traits showed nonlinear plasticity with best performance at intermediate temperatures, whereas physiology traits were generally less responsive to temperature. Variation in plasticity among families was lowest for the traits most necessary for tolerating environmental extremes (e.g. heat tolerance), suggesting that physiology traits may be canalised and fitness suffers for it. In contrast, variation in means, and plasticity in some cases, among families in germination traits suggests genetic variation and hence the potential for these few traits to respond to selection. Our results illustrate the variety of responses that may occur in response to temperature, and the frequent occurrence of complex nonlinear plastic responses that would not have been apparent with comparison of fewer temperatures. We discuss the physiological, ecological and evolutionary insights our findings provide into the response of wild species to the changing climate. Read the free Plain Language Summary for this article on the Journal blog.

Maternal Fecal Microbes Contribute to Shaping the Early Life Assembly of the Intestinal Microbiota of Co-inhabiting Yak and Cattle Calves.

The Qinghai-Tibetan Plateau offers one of the most extreme environments for yaks (Bos grunniens). Although the genetic adaptability of yak and rumen metagenomes is increasingly understood, the relative contribution of host genetics and maternal symbiotic microbes throughout early intestinal microbial successions in yaks remains elusive. In this study, we assessed the intestinal microbiota succession of co-inhabiting yak and cattle (Bos taurus) calves at different weeks after birth as well as the modes of transmission of maternal symbiotic microbes (i.e., rumen fluid, feces, oral cavity, and breast skin) to their calves’ intestinal microbiota colonization. We found that the fecal microbiota of yak and cattle calves after birth was dominated by members of the families Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae. The Source Tracker model revealed that maternal fecal microbes played an important role (the average contribution was about 80%) in the intestinal microbial colonization of yak and cattle calves at different weeks after birth. Unlike cattle calves, there was no significant difference in the fecal microbiota composition of yak calves between 5 and 9 weeks after birth (Wilcoxon test, P > 0.05), indicating that yak may adapt to its natural extreme environment to stabilize its intestinal microbiota composition. Additionally, our results also find that the intestinal microbial composition of yak and cattle calves, with age, gradually tend to become similar, and the differences between species gradually decrease. The findings of this study are vital for developing strategies to manipulate the intestinal microbiota in grazing yaks and cattle for better growth and performance on the Qinghai-Tibetan Plateau.

Simultaneous test and estimation of total genetic effect in eQTL integrative analysis through mixed models.

Integration of expression quantitative trait loci (eQTL) into genome-wide association studies (GWASs) is a promising manner to reveal functional roles of associated single-nucleotide polymorphisms (SNPs) in complex phenotypes and has become an active research field in post-GWAS era. However, how to efficiently incorporate eQTL mapping study into GWAS for prioritization of causal genes remains elusive. We herein proposed a novel method termed as Mixed transcriptome-wide association studies (TWAS) and mediated Variance estimation (MTV) by modeling the effects of cis-SNPs of a gene as a function of eQTL. MTV formulates the integrative method and TWAS within a unified framework via mixed models and therefore includes many prior methods/tests as special cases. We further justified MTV from another two statistical perspectives of mediation analysis and two-stage Mendelian randomization. Relative to existing methods, MTV is superior for pronounced features including the processing of direct effects of cis-SNPs on phenotypes, the powerful likelihood ratio test for assessment of joint effects of cis-SNPs and genetically regulated gene expression (GReX), two useful quantities to measure relative genetic contributions of GReX and cis-SNPs to phenotypic variance, and the computationally efferent parameter expansion expectation maximum algorithm. With extensive simulations, we identified that MTV correctly controlled the type I error in joint evaluation of the total genetic effect and proved more powerful to discover true association signals across various scenarios compared to existing methods. We finally applied MTV to 41 complex traits/diseases available from three GWASs and discovered many new associated genes that had otherwise been missed by existing methods. We also revealed that a small but substantial fraction of phenotypic variation was mediated by GReX. Overall, MTV constructs a robust and realistic modeling foundation for integrative omics analysis and has the advantage of offering more attractive biological interpretations of GWAS results.

Genetic analysis of hybridization between white-handed (Hylobates lar) and pileated (Hylobates pileatus) gibbons in a contact zone in Khao Yai National Park, Thailand.

Natural hybridization has played various roles in the evolutionary history of primates. Its consequences range from genetic introgression between taxa, formation of hybrid zones, and formation of new lineages. Hylobates lar, the white-handed gibbon, and Hylobates pileatus, the pileated gibbon, are largely allopatric species in Southeast Asia with a narrow contact zone in Khao Yai National Park, Thailand, which contains both parental types and hybrids. Hybrid individuals in the zone are recognizable by their intermediate pelage and vocal patterns, but have not been analyzed genetically. We analyzed mitochondrial and microsatellite DNA of 52 individuals to estimate the relative genetic contributions of the parental species to each individual, and the amount of introgression into the parental species. We obtained fecal samples from 33 H. lar, 15 H. pileatus and four phenotypically intermediate individuals in the contact zone. Both mitochondrial and microsatellite markers confirmed distinct differences between these taxa. Both H. lar and H. pileatus contributed to the maternal lineages of the hybrids based on mitochondrial analysis; hybrids were viable and present in socially normal reproductive pairs. The microsatellite analysis identified ten admixed individuals, four F1 hybrids, which corresponded to phenotypic hybrids, and six H. lar-like backcrosses. All 15 H. pileatus samples were identified as originating from genetically H. pileatus individuals with no H. lar admixture; hence, backcrossing is biased toward H. lar. A relatively low number of phenotypic hybrids and backcrossed individuals along with a high number of parental types indicates a bimodal hybrid zone, which suggests relatively strong bias in mate selection between the species.

High prevalence of sternal foramina in indigenous Bolivians compared to Midwest Americans and indigenous North Americans (sternal foramina in indigenous Bolivians).

The sternal foramen, usually an asymptomatic osteological defect, can lead to catastrophic consequences if not recognized prior to certain medical procedures. This study reports the prevalence of a sternal foramen in two South Amerindian populations compared with other published populations. We evaluated the presence of sternal foramina using thoracic computed tomography scans of 1334 (48% female) participants from two indigenous populations of Bolivia (n = 900 Tsimane, 434 Moseten). The prevalence of sternal foramina was compared to two U.S. populations of similar sex/age distribution (n = 572 Midwest Americans, 131 self-identified Native North Americans) via similar CT scans. A sternal foramen was significantly more common in the two Bolivian populations (prevalence ranging from 12.8 to 13.4%), compared to 4.4-5.1% in the two U.S. groups, consistent with prior estimates in studies from industrialized populations. Males had higher frequency of a sternal foramen compared to females in each of the four groups (OR = 1.904, 95% CI: 1.418-2.568, p < 0.001). Age was not associated with sternal foramen presence. These data show both a higher rate of sternal foramina in the South Amerindian populations versus comparator populations in North America and the highest rate of any studied living population. Although it is not possible to determine from our data the relative contribution of genetics versus early life or environmental causes to the higher rates of sternal foramen, we note that small prior studies have likewise demonstrated a higher prevalence in lower income countries. Further determination of the contributing factors warrants greater investigation and research.

Plasticity and genetic basis of cichlid gill arch anatomy reveal novel roles for Hedgehog signaling.

Teleost gill arches are exquisitely evolved to maximize foraging efficiency, and include structures for the capture, filtering, and processing of prey. While both plasticity and a genetic basis for gill arch traits have been noted, the relative contributions of genetics and the environment in shaping these structures remains poorly understood. East African cichlids are particularly useful in this line of study due to their highly diverse and plastic feeding apparatus. Here we explore the gene-by-environmental effects on cichlid GRs by rearing pure bred species and their F3 hybrids in different foraging environments. We find that anatomical differences between species are dependent on the environment. The genetic architecture of these traits is also largely distinct between foraging environments. We did, however, note a few genomic "hotspots" where multiple traits map to a common region. One of these, for GR number across multiple arches, maps to the ptch1 locus, a key component of the Hedgehog (Hh) pathway that has previously been implicated in cichlid oral jaw shape and plasticity. Since Hh signalling has not previously been implicated in GR development, we explored functional roles for this pathway. Using a small molecule inhibitor in cichlids, as well as zebrafish transgenic systems, we demonstrate that Hh levels negatively regulate GR number, and are both necessary and sufficient to maintain plasticity in this trait. In all these data underscore the critical importance of the environment in determining the relationship between genotype and phenotype, and provide a molecular inroad to better understand the origins of variation in this important foraging-related trait.

INFANT BIRTH WEIGHT AND MATERNAL BMI: GENETIC VS EPIGENETIC CONTRIBUTIONS

The prevalence of obesity is increasing worldwide. Obesity has been shown to have a negative effect on reproductive outcomes in both spontaneous and IVF pregnancies. Studies on the effect of maternal BMI on pregnancy success rates in donor oocyte IVF cycles are conflicting. Few studies have examined the effect of maternal BMI on neonatal outcomes. While increasing maternal BMI is associated with increased infant birth weight in both spontaneous and autologous IVF pregnancies, it is unclear whether this is primarily a genetic or epigenetic phenomenon. To our knowledge, this is the first study to examine the effect of donor BMI on infant birth weight in donor oocyte IVF cycles. The purpose of this study is to assess the relationship between infant birth weight and recipient and donor BMI in donor oocyte IVF cycles in order to determine the relative genetic (oocyte) and epigenetic (endometrial) contributions. IRB-approved retrospective cohort study. We conducted a retrospective cohort study of 130 donor oocyte IVF cycles resulting in a singleton live birth at a single IVF center from 2012-2018. Pearson correlation coefficients were calculated to examine the relationship between recipient and donor BMI and infant birth weight. ANOVA was conducted to compare infant weight among various BMI subgroups. Linear regression was used to adjust for the type of embryo transfer (fresh vs frozen), diabetes or gestational diabetes status, hypertension in pregnancy, gestational age, and infant sex. Recipients were >35 years of age on average and predominantly Caucasian. Decreased ovarian reserve was the most common etiology of infertility diagnosis. Forty-four percent of recipients were normal weight and 56% were overweight or obese. The mean age of oocyte donors was 26.7 ± 3.15 (Range 20-39) years. Seventy-eight percent of oocyte donors were normal weight and oocyte donors were predominantly Caucasian. There was no correlation between recipient BMI and infant birth weight (r=0; p=0.99). In contrast, there was a weakly positive, but non-significant, correlation between donor BMI and infant birth weight (r=0.02; p=0.76). This relationship persisted after adjusting for potential confounders. Several studies have shown a clear association between maternal BMI and infant birth weight in autologous IVF cycles. In this study we examined the relative contribution of donor and recipient BMIs to infant birth weight in donor oocyte IVF cycles. The lack of correlation observed between recipient BMI and infant birth weight along with the weak although not significant correlation between donor BMI and infant birth weight suggests that oocyte or genetic components may play a greater role in infant birth weight compared to epigenetic or endometrial factors. This study is limited by the relatively small sample size and lack of information on paternal BMI. Future studies aim to examine metabolic health outcomes in oocyte donor-conceived children.

Etiology of Autism Spectrum Disorders and Autistic Traits Over Time

The frequency with which autism spectrum disorders (ASDs) are diagnosed has shown a marked increase in recent years. One suggestion is that this is partly because of secular changes in the environment, yet to our knowledge this hypothesis lacks evidence. To assess whether the relative importance of genetic and environmental associations with ASD and autistic traits has changed over a 16-year and 26-year period. A twin design was used to assess whether the heritability of ASD and autistic traits has changed over time. Data from 2 nationwide Swedish twin cohorts was used: the Swedish Twin Registry (STR; participants born between January 1982 and December 2008) and the Child and Adolescent Twin Study in Sweden (CATSS; participants born between January 1992 and December 2008). Autism spectrum disorder diagnoses were identified for twins in the STR, with follow-up to 2013. Questionnaires assigned screening diagnoses of ASD to CATSS participants and assessed autistic traits. Analyses were performed from September 1, 2018, to March 31, 2019. Each sample was divided into several birth cohorts covering 1982 to 1991 (for the STR only), 1992-1995, 1996-1999, 2000-2003, and 2004-2008. We assessed whether the genetric and environment variance underlying autistic traits changed across birth cohorts and examined whether the relative contribution of genetics and environment to liability for autism changed across birth cohorts. Data were available for 22 678 twin pairs (5922 female same-sex pairs [26.1%], 5563 male same-sex pairs [24.5%], and 11193 opposite-sex pairs [49.4%]) in the STR and 15 280 pairs (4880 female same-sex pairs [31.9%], 5092 male same-sex pairs [33.3%], and 5308 opposite-sex pairs [34.7%]) in CATSS. The heritability of ASD diagnoses in the STR ranged from 0.88 (95% CI, 0.74-0.96) to 0.97 (95% CI, 0.89-0.99). The heritability of screening diagnoses in CATSS varied from 0.75 (95% CI, 0.58-0.87) to 0.93 (95% CI, 0.84-0.98). Autistic traits showed a modest variance increase over time that was associated with increases in genetic and environmental variance, with the total variance increasing from 0.95 (95% CI, 0.92-0.98) to 1.17 (95% CI, 1.13-1.21) over time. Weak evidence was found for changes in the genetic and environmental factors underlying ASD and autistic traits over time. Genetic factors played a consistently larger role than environmental factors. Environmental factors are thus unlikely to explain the increase in the prevalence of ASD.

The effect of genetic on dental anxiety: Twin study

Aim: Genetic variations contribute differences in defensive behaviors among individuals. However, the exact role of heritability in the etiology of defensive behaviors like dental anxiety is not elucidated clearly. Twin studies provide an excellent source to investigate the relative contribution of genetics and environment in various phenotypic traits or disorders. Therefore, the aim of this study is to explore the relative contribution of genetics on dental anxiety on Turkish twins by using the classical twin method. Material and Methods: Corah’s Dental Anxiety Scale used for the anxiety measurement of 70 pairs of Turkish twins. Decayed, Missing, Filled-Teeth (DMF-T) index was calculated according to the number of decayed, missing and filled teeth after clinical and radiological examinations.Results: No significant differences and correlations found within the dental anxiety scores of Monozygotic (MZ) and Dizygotic (DZ) twin-pairs. Significant positive correlation for DMF-T scores was found within the MZ and DZ twin-pairs.Conclusion: Based on the data obtained from our study, it can be concluded that environmental factor appears to have a more dominant effect on dental anxiety and the high correlation regarding DMF-T among MZ twin pairs indirectly shows the genetic effect on dental caries.

Impact of Somatic Mutations on Outcome in Patients > 60 Years Old with Newly Diagnosed AML Treated with Response-Adapted Sequential Azacitidine and Induction Chemotherapy within the DRKS00004519 Trial (RAS-AZIC) of the East German Study Group of Hematology and Oncology (OSHO)

Introduction: Old age and unfavorable cytogenetics are well-established adverse prognostic factors for outcome in patients (pts) with AML. Recently, high-throughput sequencing techniques have identified multiple somatically acquired driver mutations (muts) with a strong prognostic impact in AML. We explored the relative contribution of baseline molecular genetics versus a response-based sequential treatment approach on response and overall survival (OS) at two years in pts &amp;gt;60 years (y) with newly diagnosed AML treated within the multicenter RAS-AZIC study of the OSHO. Patients and methods: In the RAS-AZIC trial, 112 pts received priming with Azacitidine (AZA) followed by a day (d) 15 bone marrow (BM) blast count-adapted sequential treatment with AZA or intensive chemotherapy (IC). Pts with d15 blasts ≥45% received IC. If the count was &amp;lt;45%, AZA was continued at d28. The second treatment adaptation was based on d56 response. If no complete remission (CR) or CR with incomplete recovery (CRi) were documented, IC was applied followed by AZA maintenance or allogeneic hematopoietic stem cell transplantation if a remission was achieved on d90. Conventional cytogenetics, NPM1, and FLT3 mutational screening were used for genetic risk stratification following the 2010 ELN recommendations. Response [CR/CRi/Partial remission (PR)] and treatment-related mortality on d90, the two-year OS, event-free survival (EFS), and relapse-free survival (RFS) were previously presented (Jaekel N, et al; ASH 2018). Baseline BMs of 77 pts who signed the translational informed consent were analyzed by NGS using the NEOmyeloid panel of NEO New Oncology (Siemens Healthineers Company, Germany). This hybrid capture-based assay comprises 43 genes and detects point muts, small insertions and deletions in 30 genes as well as gene fusions in 18 genes. Molecular results were correlated to outcome data. Results: Median age was 70y. Secondary AML was present in 39%. Genetic risk was int-II and adverse in 25% and 27% respectively. Response on d90 was 67% (CR/CRi 58%, PR 9%). A median of 3 muts per pt were found. Mutations in DNA methylation-related-, spliceosome complex-, and chromatin-modifying-genes were 62%, 39%, and 30% respectively. Overall, muts in DNMT3A (34%), ASXL1 (25%), RUNX1 (24%), SRSF2 (23%), and TET2 (23%) were the most frequently detected (fig. 1). As expected, 72% of SRSF2 muts were associated with ASXL1 and/or RUNX1 muts. CR/CRi in the favorable and int-I 2010 ELN genetic risk groups was 81% and 57.5% in int-II and adverse risk pts. With the exception of muts in spliceosome complex-related genes, the mutational status (including the FLT3 status) seemed to have no impact on response in this cohort (table 1). In the presence of splicing factor gene muts a trend towards an inferior response of 53% compared to 77% in pts without such a mut was observed. High risk muts such as ASXL1, RUNX1, and TP53 muts which were included in the 2017 ELN adverse risk stratification were present in 20/32 (63%) of pts with favorable and int-I genetic risk. Yet, only 5/32 (16%) did not achieve a response. Similarly, CR/CRi was achieved in 7/9 (78%) pts with TP53 mut which was associated with an adverse karyotype in 8 pts. Likewise, OS tended to be similar across all molecular classes with the exception of KMT2A gene fusions with their well-known negative impact on outcome. The presence of such a fusion (n=4) was associated with a median survival time of only 8 compared to 16 months in pts without a detectable KMT2A fusion. These KMT2A gene fusions also correlated with a shorter EFS and RFS. The presence of myeloid transcription factor gene muts such as in RUNX1 (24%) and BCOR (13%) tended to be associated with an inferior EFS, while cohesin complex- (STAG2 8%), tumour suppressor-, and DNA-methylation-related gene muts with a negative RFS (table 1). Conclusions: This explorative analysis with a limited number of patients describes the pattern of genetic mutations in elderly AML treated with a response-based sequential approach that integrates epigenetic and chemotherapeutic treatments and their association with outcome. Whether such a response-based treatment mitigates the negative impact of (some) high risk mutations on outcome needs to be addressed in a much larger trial. Disclosures Jaekel: Celgene: Other: travel grant. Siebolts:Merck: Honoraria; Boehringer Ingelheim: Honoraria; MSD: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Roche: Honoraria; Novartis: Honoraria; BMS: Honoraria. Pazaitis:Novartis: Consultancy. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Hänel:Amgen: Honoraria; Roche: Honoraria; Novartis: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Heukamp:NEO New Oncology GmbH: Employment. Menon:NEO New Oncology GmbH: Employment. Bertrand:NEO New Oncology GmbH: Employment. Wickenhauser:BMS: Honoraria; Merck-Serono: Honoraria; MSD: Honoraria; Böhringer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Brosteanu:University Leipzig: Employment. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.