Genome-wide association study and polygenic risk score analysis for hearing measures in children

Funding information: Deutsche Forschungsgemeinschaft, Grant/Award Number: SCHM 3530/1-1 (418445085); Royal Society, Grant/Award Number: UF150663; UK Medical Research Council and Wellcome, Grant/Award Number: 217065/Z/19/Z; Wellcome Trust, Grant/Award Number: 105621/Z/14/ZAn efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HTs) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWASs) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by external environmental factors. Here, we investigated HT and HTA in a children population cohort (ALSPAC, n = 6,743). Better hearing was associated with better cognitive performance and higher socioeconomic status. At the group level, HTA suggested a left ear advantage (mean = −0.28 dB) that was mainly driven by females. SNP heritability for HT and HTA was 0.13 and 0.02, respectively (n = 4,989). We found a modest negative genetic correlation between HT and reading ability. GWAS for HT (n = 5,344) did not yield significant hits but polygenic risk scores for higher educational attainment (EA, ß = −1,564.72, p = .008) and schizophrenia (ß = −241.14, p = .004) were associated with lower HT, that is, better hearing. In summary, we report new data supporting associations between hearing measures and cognitive abilities at the behavioral level. Genetic analysis suggests shared biological pathways between cognitive and sensory systems and provides evidence for a positive outcome of genetic risk for schizophrenia.Publisher PDFPeer reviewe

Identifizierung von Kaiso Like 1 (Zbtb4) als negativem Regulator der P21CIP1-Expression, Interaktionspartner von Miz1 und Histondeacetylasen sowie Modulator der zellulären p53-Antwort

Kaiso Like 1 (Zbtb4) ist ein neu identifiziertes Protein, das zur Familie der BTB/POZ-Domänen-Zinkfinger-Proteine zählt. Aufgrund seiner Homologie zu dem Transkriptionsfaktor und POZ-Protein Kaiso wurde es Kaiso Like 1 benannt. Wegen seiner Gruppenzugehörigkeit zu den BTB-Proteinen wird es auch Zbtb4 genannt. Zu Beginn der vorliegenden Arbeit war über Kaiso Like 1 (KL1) einzig bekannt, dass die Expression seiner mRNA in Neuroblastomen, die mit einer schlechten Prognose einhergehen, gegenüber Neuroblastomen mit einer guten Prognose herunterreguliert ist. Eine Oncomine-Datenbankanalyse hat dieses Expressionsmuster für viele weitere solide Tumoren bestätigt. Ebenso hat sie ergeben, dass die mRNA-Expression von KL1 in soliden Tumoren im Vergleich zu Normalgewebe herunterreguliert ist. Ziel dieser Arbeit war es daher, KL1 näher zu charakterisieren, hierbei Interaktionspartner und Zielgene sowie eine mögliche biologische Funktion zu identifizieren. Zur Charakterisierung wurde KL1 im Zellkultursystem sowohl überexprimiert als auch depletiert. Eine starke Überexpression von KL1 induziert Apoptose in humanen Zelllinien, die durch eine FACS-Analyse nachgewiesen werden konnte. Zellen, die KL1 in geringen Mengen überexprimieren, sowie KL1-depletierte Zellen weisen jedoch unter normalen Zellkulturbedingungen keinen spezifischen Phänotyp im Vergleich zu Kontrollzellen auf. Um eine biologische Funktion von KL1 zu identifizieren, dessen mRNA-Expression in schlecht prognostischen Tumoren herunterreguliert ist, wurde KL1 in der Neuroblastomzelllinie SH-EP depletiert und die Zellen mit verschiedenen in der Neuroblastomtherapie eingesetzten Chemotherapeutika behandelt. KL1-depletierte Zellen überleben die Behandlung mit niedrig dosiertem Vincristin, während die Kontrollzellen absterben. Vincristin induziert keinen DNA-Schaden, sondern hemmt, niedrig dosiert, die Dynamik der Mikrotubuli. Dies führt zu einer Aktivierung von p53, welches daraufhin seine pro-apoptotischen Zielgene sowie P21CIP1 aktivieren kann, über das p53 den G1-Arrest im Zellzyklus vermittelt. In dieser Arbeit wurde die Ursache für die Resistenz KL1-depletierter Zellen herausgefunden: KL1 blockiert spezifisch den p53 induzierten G1-Arrest, indem es als Repressor die Transaktivierung seines neu identifizierten Zielgenes P21CIP1 hemmt. In KL1-depletierten Zellen entfällt diese Repression, so dass sich die p53-Antwort nach Behandlung mit niedrig dosiertem Vincristin von Apoptose in Richtung G1-Arrest mit anschließend niedriger Proliferationsrate verschiebt. Eine gleichzeitige Depletion von P21CIP1 hebt die Resistenz KL1-depletierter Zellen gegenüber Vincristin größtenteils wieder auf. Um zu zeigen, dass KL1 die p53-Antwort generell und nicht nur nach Behandlung mit Vincristin moduliert, wurden SH-EP-Zellen, die KL1 überexprimieren, sowie Kontrollzellen mit Nutlin-3, einem Stabilisator der p53-Aktivität, behandelt. Während die Kontrollzellen unter den gewählten Bedingungen mit einem G1-Arrest (nicht mit Apoptose) auf die Behandlung reagieren, durchlaufen SH-EPZellen, die KL1 überexprimieren, einen normalen Zellzyklus. Die KL1 vermittelte Repression der P21CIP1-Expression erfolgt dabei unabhängig von p53, wahrscheinlich durch Interaktion mit Miz1 und Histondeacetylase-Repressorkomplexen am P21CIP1-Promotor: In dieser Arbeit wurde gezeigt, dass die Hemmung der Histondeacetylase-Aktivität zu einer Abnahme der KL1 vermittelten Repression der P21CIP1-Expression führt und KL1 die Miz1 vermittelte Transaktivierung des P21CIP1-Promotors in Reporter-Assays blockiert. Darüber hinaus wurde in Co-Immunopräzipitationsanalysen eine Interaktion zwischen den exogenen Proteinen KL1 und Miz1 unter anderem mit der Histondeacetylase 2 nachgewiesen. Ebenso gelang der Interaktionsnachweis von KL1 und endogenem Miz1. Eine In-vivo-Bindung von KL1 an den P21CIP1-Promotor und eine In-vitro-Bindung von KL1 an KL1-Bindungssequenzen des P21CIP1-Promotors sowie an Miz1-Bindungssequenzen, wenn Miz1 co-exprimiert wurde, konnte ebenso nachgewiesen werden. In dieser Doktorarbeit wurde KL1 über die Hemmung von P21CIP1 als ein weiterer Faktor in Neuroblastomzellen identifiziert, der die p53-Antwort kontrolliert. Andere Studien zeigen, dass p21Cip1 je nach zellulärem Kontext eine Funktion als Tumorsuppressor oder als Onkogen ausüben kann. KL1 als Repressor der P21CIP1-Expression könnte demnach die onkogene Funktion von p21Cip1 in soliden Tumoren hemmen. Darin könnte der Grund für die Herunterregulation der KL1-mRNA-Expression liegen. Als therapeutisches target eignet sich KL1 jedoch nicht generell. Die Herunterregulation seiner Expression führt nur spezifisch zu einer Resistenz gegenüber niedrig dosiertem Vincristin und nicht gegenüber anderen in der Neuroblastomtherapie eingesetzten Chemotherapeutika. Ursache hierfür ist, dass DNA schädigende Chemotherapeutika nicht nur einen p53 vermittelten G1-Arrest induzieren, der durch KL1 über Hemmung der P21CIP1-Expression blockiert werden kann, sondern auch einen G2-Arrest, der unabhängig von p21Cip1 ist

Identification of loci involved in childhood visual acuity and associations with cognitive skills and educational attainment

Funding: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. JS is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 418445085) and supported by the Wellcome Trust [Institutional Strategic Support fund, Grant number 204821/Z/16/Z]. SP is funded by the Royal Society (UF150663). Support to the genetic analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 105621/Z/14/Z].Visual acuity significantly contributes to quality of life. Deficits in childhood are associated with reading difficulties, which can have detrimental effects on education outcomes. In adults, it has been observed that vision defects such as myopia are associated with higher educational attainment (EA). Understanding genetic factors contributing to visual acuity could help to dissect its links with cognitive skills, neurodevelopmental conditions, and education. We examined associations between distance visual acuity, cognitive measures including school grades, and neurodevelopmental conditions in a longitudinal cohort of British children (ALSPAC, n = 6807, M age = 11.8). We performed a genome-wide association study (GWAS, n = 5571) on visual acuity and tested for genetic associations with relevant phenotypes using polygenic scores (PGS) and genetic correlation analyses. Visual acuity was associated with better cognitive performance and school grades, and reduced in individuals with reading difficulties compared to controls. GWAS revealed genetic associations at the NPLOC4 locus and highlighted other genes involved in sensory function. In line with positive genetic correlations between visual acuity and cognitive measures, EA PGS were positively associated with visual acuity, while there was a less robust negative association with myopia PGS. In conclusion, increased visual acuity is associated with a range of positive outcomes, including better school grades. Our results suggest an association between a higher EA PGS and slightly increased visual acuity in childhood. This could indicate gene-environment correlation, in which environmental exposures linked to higher EA might have detrimental effects on vision offsetting the initial positive effect.Publisher PDFPeer reviewe

Building an Asymmetrical Brain: The Molecular Perspective

The brain is one of the most prominent examples for structural and functional differences between the left and right half of the body. For handedness and language lateralization, the most widely investigated behavioral phenotypes, only a small fraction of phenotypic variance has been explained by molecular genetic studies. Due to environmental factors presumably also playing a role in their ontogenesis and based on first molecular evidence, it has been suggested that functional hemispheric asymmetries are partly under epigenetic control. This review article aims to elucidate the molecular factors underlying hemispheric asymmetries and their association with inner organ asymmetries. While we previously suggested that epigenetic mechanisms might partly account for the missing heritability of handedness, this article extends this idea by suggesting possible alternatives for transgenerational transmission of epigenetic states that do not require germ line epigenetic transmission. This is in line with a multifactorial model of hemispheric asymmetries, integrating genetic, environmental, and epigenetic influencing factors in their ontogenesis

Handedness in twins : meta-analyses

Funding: Open Access funding enabled and organized by Projekt DEAL. JS is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 418445085). SP is funded by the Royal Society (UF150663).Background: In the general population, 10.6% of people favor their left hand over the right for motor tasks. Previous research suggests higher prevalence of atypical (left-, mixed-, or non-right-) handedness in (i) twins compared to singletons, and in (ii) monozygotic compared to dizygotic twins. Moreover, (iii) studies have shown a higher rate of handedness concordance in monozygotic compared to dizygotic twins, in line with genetic factors playing a role for handedness. Methods: By means of a systematic review, we identified 59 studies from previous literature and performed three sets of random effects meta-analyses on (i) twin-to-singleton Odds Ratios (21 studies, n = 189,422 individuals) and (ii) monozygotic-to-dizygotic twin Odds Ratios (48 studies, n = 63,295 individuals), both times for prevalence of left-, mixed-, and non-right-handedness. For monozygotic and dizygotic twin pairs we compared (iii) handedness concordance Odds Ratios (44 studies, n = 36,217 twin pairs). We also tested for potential effects of moderating variables, such as sex, age, the method used to assess handedness, and the twins’ zygosity. Results: We found (i) evidence for higher prevalence of left- (Odds Ratio = 1.40, 95% Confidence Interval = [1.26, 1.57]) and non-right- (Odds Ratio = 1.36, 95% Confidence Interval = [1.22, 1.52]), but not mixed-handedness (Odds Ratio = 1.08, 95% Confidence Interval = [0.52, 2.27]) among twins compared to singletons. We further showed a decrease in Odds Ratios in more recent studies (post-1975: Odds Ratio = 1.30, 95% Confidence Interval = [1.17, 1.45]) compared to earlier studies (pre-1975: Odds Ratio = 1.90, 95% Confidence Interval = [1.59–2.27]). While there was (ii) no difference between monozygotic and dizygotic twins regarding prevalence of left- (Odds Ratio = 0.98, 95% Confidence Interval = [0.89, 1.07]), mixed- (Odds Ratio = 0.96, 95% Confidence Interval = [0.46, 1.99]), or non-right-handedness (Odds Ratio = 1.01, 95% Confidence Interval = [0.91, 1.12]), we found that (iii) handedness concordance was elevated among monozygotic compared to dizygotic twin pairs (Odds Ratio = 1.11, 95% Confidence Interval = [1.06, 1.18]). By means of moderator analyses, we did not find evidence for effects of potentially confounding variables. Conclusion: We provide the largest and most comprehensive meta-analysis on handedness in twins. Although a raw, unadjusted analysis found a higher prevalence of left- and non-right-, but not mixed-handedness among twins compared to singletons, left-handedness was substantially more prevalent in earlier than in more recent studies. The single large, recent study which included birth weight, Apgar score and gestational age as covariates found no twin-singleton difference in handedness rate, but these covariates could not be included in the present meta-analysis. Together, the secular shift and the influence of covariates probably make it unsafe to conclude that twinning has a genuine relationship to handedness.Publisher PDFPeer reviewe

Four meta-analyses across 164 studies on atypical footedness prevalence and its relation to handedness

Funding: Deutsche Forschungsgemeinschaft (DFG) through the Research Training Group “Situated Cognition” (GRK 2185/1) and Grant number OC 127/9-1. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and S.P. and J.S. will serve as guarantors for the analysis of the ALSPAC data presented in this paper. J.S. is funded by the DFG (Project number: 418445085). S.P. is funded by the Royal Society. D.P.C. is funded by the Leverhulme Trust. Open Access funding was provided by Projekt DEAL. We acknowledge the support by the DFG Open Access Publication Funds of the Ruhr-Universität Bochum.Human lateral preferences, such as handedness and footedness, have interested researchers for decades due to their pronounced asymmetries at the population level. While there are good estimates on the prevalence of handedness in the population, there is no large-scale estimation on the prevalence of footedness. Furthermore, the relationship between footedness and handedness still remains elusive. Here, we conducted meta-analyses with four different classification systems for footedness on 145,135 individuals across 164 studies including new data from the ALSPAC cohort. The study aimed to determine a reliable point estimate of footedness, to study the association between footedness and handedness, and to investigate moderating factors influencing footedness. We showed that the prevalence of atypical footedness ranges between 12.10% using the most conservative criterion of left-footedness to 23.7% including all left- and mixed-footers as a single non-right category. As many as 60.1% of left-handers were left-footed whereas only 3.2% of right-handers were left-footed. Males were 4.1% more often non-right-footed compared to females. Individuals with psychiatric and neurodevelopmental disorders exhibited a higher prevalence of non-right-footedness. Furthermore, the presence of mixed-footedness was higher in children compared to adults and left-footedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally influenced by cultural and social factors, which play a crucial role in the determination of handedness. Overall, this study provides new and useful reference data for laterality research. Furthermore, the data suggest that footedness is a valuable phenotype for the study of lateral motor biases, its underlying genetics and neurodevelopment.Publisher PDFPeer reviewe

Human handedness : a meta-analysis

Silvia Paracchini is a Royal Society University Research Fellow. Judith Schmitz is a DFG fellow and received funding from the School of Medicine, University of St Andrews for this specific work.Across time and place, right hand preference has been the norm, but what is the precise prevalence of left- and right-handedness? Frequency of left-handedness has shaped and underpinned different fields of research, from cognitive neuroscience to human evolution, but reliable distributional estimates are still lacking. While hundreds of empirical studies have assessed handedness, a large-scale, comprehensive review of the prevalence of handedness and the factors that moderate it, is currently missing. Here, we report 5 meta-analyses on hand preference for different manual tasks and show that left-handedness prevalence lies between 9.3% (using the most stringent criterion of left-handedness) to 18.1% (using the most lenient criterion of nonright-handedness), with the best overall estimate being 10.6% (10.4% when excluding studies assessing elite athletes’ handedness). Handedness variability depends on (a) study characteristics, namely year of publication and ways to measure and classify handedness, and (b) participant characteristics, namely sex and ancestry. Our analysis identifies the role of moderators that require taking into account in future studies on handedness and hemispheric asymmetries. We argue that the same evolutionary mechanisms should apply across geographical regions to maintain the roughly 1:10 ratio, while cultural factors, such as pressure against left-hand use, moderate the magnitude of the prevalence of left-handedness. Although handedness appears as a straightforward trait, there is no universal agreement on how to assess it. Therefore, we urge researchers to fully report study and participant characteristics as well as the detailed procedure by which handedness was assessed and make raw data publicly available.PostprintPeer reviewe

Quantitative multidimensional phenotypes improve genetic analysis of laterality traits

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and SP and JS will serve as guarantors for the analysis of the ALSPAC data presented in this paper. GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Support to the genetic analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 105621/Z/14/Z]. The Hong Kong sample was funded through a Collaborative Research Fund from the Hong Kong Special Administrative Region Research Grants Council (CUHK8/CRF/13G, and C4054-17WF). JS is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 418445085) and supported by the Wellcome Trust [Institutional Strategic Support fund, Grant number 204821/Z/16/Z]. SP is funded by the Royal Society (UF150663).Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h2, n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits.Publisher PDFPeer reviewe

Risk-Adjusted Cancer Screening and Prevention (RiskAP): Complementing Screening for Early Disease Detection by a Learning Screening Based on Risk Factors

Breast cancer; Evidence-generating care; Risk-adjusted preventionCáncer de mama; Atención generadora de evidencia; Prevención ajustada al riesgoCàncer de mama; Atenció generadora d'evidències; Prevenció ajustada al riscBackground: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.The project was funded by the German Federal Ministry of Health (grant No. 2515FSB401 to Rita Schmutzler and Christiane Woopen) for supporting the international expert meetings, and a grant of the EU Horizon 2020 program, BRIDGES (grant No. 634935, PI Peter Devilee, WP5-PI Rita Schmutzler), for the compilation of the most recent findings of genetic risk prediction

A GWAS for grip strength in cohorts of children—advantages of analysing young participants for this trait

Funding: Royal Society. Grant Numbers: RGF\EA\180141, UF150663; Medical Research Scotland. Grant Number: PhD-50010-2019; Medical Research Council. Grant Number: 102215/2/13/2; Wellcome Trust. Grant Numbers: 105621/Z/14/Z, 204821/Z/16/Z; National Health and Medical Research Council of Australia (NHMRC). Grant Numbers: 1059711, 403981, 572613; Deutsche Forschungsgemeinschaft. Grant Number: 418445085.Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genome-wide association studies (GWASs) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5450; age range = 10.65–13.61; Raine Study, N = 1162, age range: 9.42–12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e−08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an expression quantitative trait locus (eQTL) effect. Despite a much smaller sample (~3%) compared with the UK Biobank we replicated correlation analyses previously reported in this much larger adult cohort, such as a negative correlation with coronary artery disease. Although the results from the polygenic risk score (PRS) analyses did not survive multiple testing correction, we observed nominally significant associations between GS and risk of overall fracture, as previously reported, as well ADHD which will require further investigations. Finally, we observed a higher SNP-heritability (24%–41%) compared with previous studies (4%–24%) in adults. Overall, our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared with adults.Peer reviewe