RESUMEN
Parent scientists lead a journey to bring surveillance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to public schools across the state of Massachusetts and beyond.
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COVID-19/diagnóstico , Personal de Laboratorio , Padres , COVID-19/virología , Prueba de COVID-19 , Conducta Cooperativa , Educación , Humanos , Massachusetts , SARS-CoV-2/fisiologíaRESUMEN
Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 µL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
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Sangre Fetal/inmunología , Sistema Inmunológico/fisiología , Recien Nacido Prematuro/inmunología , Inflamación , Linaje de la Célula , Disbiosis , Femenino , Microbioma Gastrointestinal , Humanos , Inmunoensayo , Recién Nacido , Leucocitos Mononucleares/metabolismo , Estudios Longitudinales , Masculino , Padres , Fenotipo , Nacimiento Prematuro/inmunología , TranscriptomaRESUMEN
Human papillomavirus (HPV) is currently linked to almost 35,000 new cases of cancer in women and men each year in the United States. Gardasil-9 (Merck & Company), the only HPV vaccine now available in the United States, is nearly 100% effective at preventing precancers caused by oncogenic HPV types. In the United States, however, only about one half of adolescents are up to date with HPV vaccination. It is well known that health care clinicians' recommendations play a significant role in parents' decisions regarding HPV vaccination. A growing body of literature examines specific communication strategies for promoting uptake of the HPV vaccine. A comprehensive review of the evidence for each of these strategies is needed. The authors searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Web of Science Complete databases for original articles with a defined clinician communication strategy and an outcome of HPV vaccine uptake or intention to vaccinate (PROSPERO registry no. CRD42020107602). In total, 46 studies were included. The authors identified two main strategies with strong evidence supporting their positive impact on vaccine uptake: strong recommendation and presumptive recommendation. Determinations about a causal relationship were limited by the small numbers of randomized controlled trials. There is also opportunity for more research to determine the effects of motivational interviewing and cancer-prevention messaging.
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Alphapapillomavirus , Neoplasias , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Adolescente , Masculino , Femenino , Humanos , Estados Unidos , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/complicaciones , Vacunas contra Papillomavirus/uso terapéutico , Vacunación , Comunicación , Padres , Neoplasias/prevención & controlRESUMEN
Mutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individual's genome1,2. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with a hypermutated genome with between two and seven times more de novo single-nucleotide variants than expected. In most families (9 out of 12), the excess mutations came from the father. Two families had genetic drivers of germline hypermutation, with fathers carrying damaging genetic variation in DNA-repair genes. For five of the families, paternal exposure to chemotherapeutic agents before conception was probably a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease.
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Enfermedades Genéticas Congénitas , Células Germinativas , Mutación de Línea Germinal , Factores de Edad , Enfermedades Genéticas Congénitas/genética , Mutación de Línea Germinal/genética , Humanos , Masculino , Mutagénesis/genética , Mutación , Padres , Polimorfismo de Nucleótido SimpleRESUMEN
Gene expression programmes conferring cellular identity are achieved through the organization of chromatin structures that either facilitate or impede transcription. Among the key determinants of chromatin organization are the histone modifications that correlate with a given transcriptional status and chromatin state. Until recently, the details for the segregation of nucleosomes on DNA replication and their implications in re-establishing heritable chromatin domains remained unclear. Here, we review recent findings detailing the local segregation of parental nucleosomes and highlight important advances as to how histone methyltransferases associated with the establishment of repressive chromatin domains facilitate epigenetic inheritance.
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Linaje de la Célula , Ensamble y Desensamble de Cromatina , Replicación del ADN , Epigénesis Genética , Patrón de Herencia , Nucleosomas/metabolismo , Humanos , Nucleosomas/genética , PadresRESUMEN
This paper examines whether school COVID-19 policies influenced enrollment differently by student age and race/ethnicity. Unlike much prior research, we i) analyze enrollments for virtually the entire U.S. public school population for both the 2020-2021 and 2021-2022 school years, ii) compare enrollment trends within districts in order to isolate subgroup heterogeneity from district characteristics, and iii) account for district selection into preferred learning modes. Analyzing data on over 9,000 districts that serve more than 90% of public school students in the United States, we find enrollment responses to COVID policies differed notably. We find that White enrollments declined more than Black, Hispanic, and Asian enrollments in districts that started the 2020-2021 school year virtually, but in districts that started in-person the reverse was true: Non-White enrollments declined more than White enrollments. Moreover, Black, Hispanic, and Asian families responded more than White families to higher COVID-19 death rates in the months preceding the start of the 2021 school year. In 2021-2022, enrollment differences by the previous year's learning mode persisted. Racial/ethnic differences did not vary by whether the district required masking in classrooms. These findings are consistent with the greater risk faced by communities of color during the pandemic and demonstrate an additional source of disparate impact from COVID policies.
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COVID-19 , Humanos , Factores Raciales , COVID-19/epidemiología , Escolaridad , Padres , PolíticasRESUMEN
Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.
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Revelación , Asesoramiento Genético , Niño , Humanos , Pruebas Genéticas , Padres , GenómicaRESUMEN
We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.
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Trastorno Autístico , Trastorno Bipolar , Niño , Humanos , Virulencia , Padres , Familia , Trastorno Autístico/genética , Trastorno Bipolar/genéticaRESUMEN
Paternal and maternal epigenomes undergo marked changes after fertilization1. Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications2-4 and differences in chromosome organization and accessibility, both in gametes5-8 and after fertilization5,8-10. However, these studies have led to very different conclusions: the global absence of local topological-associated domains (TADs) in gametes and their appearance in the embryo8,9 versus the pre-existence of TADs and loops in the zygote5,11. The questions of whether parental structures can be inherited in the newly formed embryo and how these structures might relate to allele-specific gene regulation remain open. Here we map genomic interactions for each parental genome (including the X chromosome), using an optimized single-cell high-throughput chromosome conformation capture (HiC) protocol12,13, during preimplantation in the mouse. We integrate chromosome organization with allelic expression states and chromatin marks, and reveal that higher-order chromatin structure after fertilization coincides with an allele-specific enrichment of methylation of histone H3 at lysine 27. These early parental-specific domains correlate with gene repression and participate in parentally biased gene expression-including in recently described, transiently imprinted loci14. We also find TADs that arise in a non-parental-specific manner during a second wave of genome assembly. These de novo domains are associated with active chromatin. Finally, we obtain insights into the relationship between TADs and gene expression by investigating structural changes to the paternal X chromosome before and during X chromosome inactivation in preimplantation female embryos15. We find that TADs are lost as genes become silenced on the paternal X chromosome but linger in regions that escape X chromosome inactivation. These findings demonstrate the complex dynamics of three-dimensional genome organization and gene expression during early development.
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Blastocisto/citología , Blastocisto/metabolismo , Cromatina/metabolismo , Desarrollo Embrionario/genética , Fertilización/genética , Células Germinativas/citología , Padres , Alelos , Animales , Cromatina/química , Cromatina/genética , Posicionamiento de Cromosoma , Cromosomas de los Mamíferos/química , Cromosomas de los Mamíferos/genética , Cromosomas de los Mamíferos/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Genoma/genética , Impresión Genómica , Células Germinativas/metabolismo , Histonas/química , Histonas/metabolismo , Masculino , Metilación , Ratones , Proteínas del Grupo Polycomb/metabolismo , Análisis de la Célula Individual , Inactivación del Cromosoma X/genéticaRESUMEN
Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.
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Trastorno del Espectro Autista , Trastornos del Desarrollo del Lenguaje , Niño , Humanos , Trastorno del Espectro Autista/genética , Herencia Multifactorial/genética , Padres , Secuenciación Completa del Genoma , Predisposición Genética a la EnfermedadRESUMEN
Mammalian infants depend on parental care for survival, with numerous consequences for their behavioral development. We investigated the epigenetic and neurodevelopmental mechanisms mediating the impact of early biparental care on development of alloparenting behavior, or caring for offspring that are not one's own. We find that receiving high parental care early in life leads to slower epigenetic aging of both sexes and widespread male-specific differential expression of genes related to synaptic transmission and autism in the nucleus accumbens. Examination of parental care composition indicates that high-care fathers promote a male-specific increase in excitatory synapses and increases in pup retrieval behavior as juveniles. Interestingly, females raised by high-care fathers have the opposite behavioral response and display fewer pup retrievals. These results support the concept that neurodevelopmental trajectories are programmed by different features of early-life parental care and reveal that male neurodevelopmental processes are uniquely sensitive to care by fathers.
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Conducta Animal , Padre , Humanos , Femenino , Animales , Masculino , Conducta Animal/fisiología , Conducta Materna/fisiología , Núcleo Accumbens , Padres , Conducta Paterna , Arvicolinae/fisiologíaRESUMEN
We investigated indirect genetic effects (IGEs), also known as genetic nurture, in education with a novel approach that uses phased data to include parent-offspring pairs in the transmitted/nontransmitted study design. This method increases the power to detect IGEs, enhances the generalizability of the findings, and allows for the study of effects by parent-of-origin. We validated and applied this method in a family-based subsample of adolescents and adults from the Lifelines Cohort Study in the Netherlands (N = 6147), using the latest genome-wide association study data on educational attainment to construct polygenic scores (PGS). Our results indicated that IGEs play a role in education outcomes in the Netherlands: we found significant associations of the nontransmitted PGS with secondary school level in youth between 13 and 24 years old as well as with education attainment and years of education in adults over 25 years old (ß = 0.14, 0.17 and 0.26, respectively), with tentative evidence for larger maternal IGEs. In conclusion, we replicated previous findings and showed that including parent-offspring pairs in addition to trios in the transmitted/nontransmitted design can benefit future studies of parental IGEs in a wide range of outcomes.
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Escolaridad , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Humanos , Adolescente , Femenino , Masculino , Adulto , Estudio de Asociación del Genoma Completo/métodos , Países Bajos , Padres , Adulto Joven , Estudios de Cohortes , Modelos GenéticosRESUMEN
Maternal immune activation (MIA) and infection during pregnancy are known to reprogramme offspring phenotypes. However, the epigenetic effects of preconceptual paternal infection and paternal immune activation (PIA) are not currently well understood. Recent reports show that paternal infection and immune activation can affect offspring phenotypes, particularly brain function, behaviour, and immune system functioning, across multiple generations without re-exposure to infection. Evidence from other environmental exposures indicates that epigenetic inheritance also occurs in humans. Given the growing impact of the coronavirus disease 2019 (COVID-19) pandemic, it is imperative that we investigate all of the potential epigenetic mechanisms and multigenerational phenotypes that may arise from both maternal and paternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as associated MIA, PIA, and inflammation. This will allow us to understand and, if necessary, mitigate any potential changes in disease susceptibility in the children, and grandchildren, of affected parents.
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COVID-19 , SARS-CoV-2 , COVID-19/genética , Susceptibilidad a Enfermedades , Epigénesis Genética , Femenino , Humanos , Padres , Embarazo , SARS-CoV-2/genéticaRESUMEN
Population genetic analyses of local ancestry tracts routinely assume that the ancestral admixture process is identical for both parents of an individual, an assumption that may be invalid when considering recent admixture. Here, we present Parental Admixture Proportion Inference (PAPI), a Bayesian tool for inferring the admixture proportions and admixture times for each parent of a single admixed individual. PAPI analyzes unphased local ancestry tracts and has two components: a binomial model that leverages genome-wide ancestry fractions to infer parental admixture proportions and a hidden Markov model (HMM) that infers admixture times from tract lengths. Crucially, the HMM accounts for unobserved within-ancestry recombination by approximating the pedigree crossover dynamics, enabling inference of parental admixture times. In simulations, we find that PAPI's admixture proportion estimates deviate from the truth by 0.047 on average, outperforming ANCESTOR and PedMix by 46.0% and 57.6%, respectively. Moreover, PAPI's admixture time estimates were strongly correlated with the truth (R=0.76) but have an average downward bias of 1.01 generations that is partly attributable to inaccuracies in local ancestry inference. As an illustration of its utility, we ran PAPI on African American genotypes from the PAGE study (N = 5,786) and found strong evidence of assortative mating by ancestry proportion: couples' ancestry proportions are highly correlated (R = 0.87) and are closer to each other than expected under random mating (p < 10-6). We anticipate that PAPI will be useful in studying the population dynamics of admixture and will also be of interest to individuals seeking to learn about their personal genealogies.
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Negro o Afroamericano , Genética de Población , Teorema de Bayes , Humanos , Padres , LinajeRESUMEN
BACKGROUND: De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. RESULTS: Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. CONCLUSION: This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.
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Células Germinativas , Padres , Humanos , MutaciónRESUMEN
Attentional reorienting is dysfunctional not only in children with autism spectrum disorder (ASD), but also in infants who will develop ASD, thus constituting a potential causal factor of future social interaction and communication abilities. Following the research domain criteria framework, we hypothesized that the presence of subclinical autistic traits in parents should lead to atypical infants' attentional reorienting, which in turn should impact on their future socio-communication behavior in toddlerhood. During an attentional cueing task, we measured the saccadic latencies in a large sample (total enrolled n = 89; final sample n = 71) of 8-month-old infants from the general population as a proxy for their stimulus-driven attention. Infants were grouped in a high parental traits (HPT; n = 23) or in a low parental traits (LPT; n = 48) group, according to the degree of autistic traits self-reported by their parents. Infants (n = 33) were then longitudinally followed to test their socio-communicative behaviors at 21 months. Results show a sluggish reorienting system, which was a longitudinal predictor of future socio-communicative skills at 21 months. Our combined transgenerational and longitudinal findings suggest that the early functionality of the stimulus-driven attentional network-redirecting attention from one event to another-could be directly connected to future social and communication development.
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Atención , Padres , Humanos , Masculino , Femenino , Lactante , Atención/fisiología , Padres/psicología , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/psicología , Conducta Social , Comunicación , Estudios Longitudinales , Trastorno Autístico/psicología , Trastorno Autístico/fisiopatología , Señales (Psicología) , Movimientos Sacádicos/fisiología , AdultoRESUMEN
Parental feedback affects children in multiple ways. However, little is known about how children, family, and feedback types affect parental feedback neural mechanisms. The current study used functional near-infrared spectroscopy-based hyperscanning to observe 47 mother-daughter pairs's (mean age of mothers: 35.95 ± 3.99 yr old; mean age of daughters: 6.97 ± 0.75 yr old) brain synchronization in a jigsaw game under various conditions. Between parental negative feedback and praise conditions, mother-daughter brain in supramarginal gyrus, left dorsolateral prefrontal cortex, right inferior frontal gyrus, and right primary somatic (S1) differed. When criticized, conformity family-communication-patterned families had much worse brain synchronization in S1, left dorsolateral prefrontal cortex, and right Wernicke's region than conversational families. Resilient children had better mother-child supramarginal gyrus synchronicity under negative feedback. This study supports the importance of studying children's neurological development in nurturing environments to assess their psychological development.
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Encéfalo , Corteza Prefrontal , Femenino , Humanos , Retroalimentación , Corteza Prefrontal/diagnóstico por imagen , Padres , Madres , Mapeo EncefálicoRESUMEN
Infants are born into networks of individuals who are socially connected. How do infants begin learning which individuals are their own potential social partners? Using digitally edited videos, we showed 12-mo-old infants' social interactions between unknown individuals and their own parents. In studies 1 to 4, after their parent showed affiliation toward one puppet, infants expected that puppet to engage with them. In study 5, infants made the reverse inference; after a puppet engaged with them, the infants expected that puppet to respond to their parent. In each study, infants' inferences were specific to social interactions that involved their own parent as opposed to another infant's parent. Thus, infants combine observation of social interactions with knowledge of their preexisting relationship with their parent to discover which newly encountered individuals are potential social partners for themselves and their families.
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Aprendizaje , Padres , Interacción Social , Humanos , LactanteRESUMEN
Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g. parental educational attainment), but the extent to which siblings affect each other is currently unclear. Here we used data from samples of unrelated individuals, without (singletons) and with biological full-siblings (non-singletons), to investigate and estimate sibling effects. Indirect genetic effects of siblings increase (or decrease) the covariance between genetic variation and a phenotype. It follows that differences in genetic association estimates between singletons and non-singletons could indicate indirect genetic effects of siblings if there is no heterogeneity in other sources of genetic association between singletons and non-singletons. We used UK Biobank data to estimate polygenic score (PGS) associations for height, BMI and educational attainment in self-reported singletons (N = 50,143) and non-singletons (N = 328,549). The educational attainment PGS association estimate was 12% larger (95% C.I. 3%, 21%) in the non-singleton sample than in the singleton sample, but the height and BMI PGS associations were consistent. Birth order data suggested that the difference in educational attainment PGS associations was driven by individuals with older siblings rather than firstborns. The relationship between number of siblings and educational attainment PGS associations was non-linear; PGS associations were 24% smaller in individuals with 6 or more siblings compared to the rest of the sample (95% C.I. 11%, 38%). We estimate that a 1 SD increase in sibling educational attainment PGS corresponds to a 0.025 year increase in the index individual's years in schooling (95% C.I. 0.013, 0.036). Our results suggest that older siblings may influence the educational attainment of younger siblings, adding to the growing evidence that effects of the environment on phenotypic variation partially reflect social effects of germline genetic variation in relatives.