Ultra-rare disruptive and damaging mutations influence educational attainment in the general population.
Ontology highlight
ABSTRACT:
SUBMITTER: Ganna A
PROVIDER: S-EPMC5127781 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
Publications
Ultra-rare disruptive and damaging mutations influence educational attainment in the general population.
Ganna Andrea A Genovese Giulio G Howrigan Daniel P DP Byrnes Andrea A Kurki Mitja M Zekavat Seyedeh M SM Whelan Christopher W CW Kals Mart M Nivard Michel G MG Bloemendal Alex A Bloom Jonathan M JM Goldstein Jacqueline I JI Poterba Timothy T Seed Cotton C Handsaker Robert E RE Natarajan Pradeep P Mägi Reedik R Gage Diane D Robinson Elise B EB Metspalu Andres A Salomaa Veikko V Suvisaari Jaana J Purcell Shaun M SM Sklar Pamela P Kathiresan Sekar S Daly Mark J MJ McCarroll Steven A SA Sullivan Patrick F PF Palotie Aarno A Esko Tõnu T Hultman Christina C Neale Benjamin M BM
Nature neuroscience 20161003 12
Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants o ...[more]
Similar Datasets
Project description:Children whose parents divorce tend to have worse educational outcomes than children whose parents stay married. However, not all children respond identically to their parents divorcing. We focus on how the impact of parental divorce on children's education varies by how likely or unlikely divorce was for those parents. We find a significant negative effect of parental divorce on educational attainment, particularly college attendance and completion, among children whose parents were unlikely to divorce. Families expecting marital stability, unprepared for disruption, may experience considerable adjustment difficulties when divorce occurs, leading to negative outcomes for children. By contrast, we find no effect of parental divorce among children whose parents were likely to divorce. Children of high-risk marriages, who face many social disadvantages over childhood irrespective of parental marital status, may anticipate or otherwise accommodate to the dissolution of their parents' marriage. Our results suggest that family disruption does not uniformly disrupt children's attainment.
| S-EPMC6462058 | biostudies-literature
Project description:Using twin (6,105 twin pairs) and genomic (5,825 unrelated individuals taken from the twin sample) analyses, we tested for genetic influences on the parent-offspring correspondence in educational attainment. Genetics accounted for nearly half of the variance in intergenerational educational attainment. A genomewide polygenic score (GPS) for years of education was also associated with intergenerational educational attainment: The highest and lowest GPS means were found for offspring in stably educated families (i.e., who had taken A Levels and had a university-educated parent; M = 0.43, SD = 0.97) and stably uneducated families (i.e., who had not taken A Levels and had no university-educated parent; M = -0.19, SD = 0.97). The average GPSs fell in between for children who were upwardly mobile (i.e., who had taken A Levels but had no university-educated parent; M = 0.05, SD = 0.96) and children who were downwardly mobile (i.e., who had not taken A Levels but had a university-educated parent; M = 0.28, SD = 1.03). Genetic influences on intergenerational educational attainment can be viewed as an index of equality of educational opportunity.
| S-EPMC5595239 | biostudies-literature
Project description:Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.
| S-EPMC8106299 | biostudies-literature
Project description:The brain is the organ of thought. The word thought is defined as the act of thinking about or considering something: an idea or opinion, or a set of ideas about a particular subject. It implicitly includes the processes of learning. Mental functions, including most if not all aspects of human behavior, such as those related to learning, arise from the activity of the brain. Neural connections that generate and support mental functions are formed throughout life, which enables lifelong learning of new concepts and skills. Both brain formation and function, as well as neural plasticity, are influenced by the activity of a variety of genes and also by epigenetic modifications, which contribute to the regulation of gene expression by adapting it to environmental conditions. In this review, aimed especially at education professionals, I discuss the genetic and epigenetic contributions to mental aspects related to learning processes in terms of heritability. I will argue that, despite most if not all aspects related to learning having a clear genetic background, innate abilities can be enhanced or diminished through educational processes. Thus, the importance of education, in the context of the inheritability of learning processes, will be discussed. The conclusion I draw is that, despite the relatively high genetic heritability shown in most brain processes associated with learning, educational practices are a key contributor to student development, allowing genetically based skills to be enhanced or alternatively diminished. Therefore one of the main goals of education in a changing an uncertain world should be to form adaptable and versatile people who can, and want to, make the most of their capabilities. Thus, knowledge derived from genetics and epigenetics, as well as from neuroscience, should be used to enhance education professionals' understanding of the biological origins of differences in mental capabilities, thereby empowering them with the possibility to adopt more respectful and flexible educational practices to attain the goal mentioned above.
| S-EPMC6635910 | biostudies-literature
Project description:Rare heritable syndromes may affect educational attainment. Here, we study education in neurofibromatosis 1 (NF1) that is associated with multifaceted medical, social and cognitive consequences. Educational attainment in the Finnish population-based cohort of 1408 individuals with verified NF1 was compared with matched controls using Cox proportional hazards model with delayed entry and competing risk for death. Moreover, models accounting for the effects of cancer at age 15-30 years, parental NF1 and developmental disorders were constructed. Overall, the attainment of secondary education was reduced in individuals with NF1 compared to controls (hazard ratio 0.83, 95%CI 0.74-0.92). History of cancer and developmental disorders were major predictors of lack of secondary education. Individuals with NF1 obtained vocational secondary education more often than general upper secondary education. Consequently, NF1 decreased the attainment of Bachelor's and Master's degrees by 46%-49% and 64%-74%, respectively. Surprisingly, the non-NF1 siblings of individuals with NF1 also had lower educational attainment than controls, irrespective of parental NF1. In conclusion, NF1 is associated with reduced educational attainment and tendency for affected individuals to obtain vocational instead of academic education. Individuals living with NF1, especially those with cancer, developmental disorders or familial NF1, need effective student counseling and learning assistance.
| S-EPMC8247857 | biostudies-literature
Project description:Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
| S-EPMC4136494 | biostudies-literature
Project description:Objective: Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.Methods: To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.Results: An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of 'binge-like' eating.Conclusions: These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.
| S-EPMC5573281 | biostudies-literature
Project description:Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 × 10-8). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu255h(+/-) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes.
| S-EPMC5187424 | biostudies-literature
Project description:Next-generation DNA sequencing promises to revolutionize clinical medicine and basic research. However, while this technology has the capacity to generate hundreds of billions of nucleotides of DNA sequence in a single experiment, the error rate of ~1% results in hundreds of millions of sequencing mistakes. These scattered errors can be tolerated in some applications but become extremely problematic when "deep sequencing" genetically heterogeneous mixtures, such as tumors or mixed microbial populations. To overcome limitations in sequencing accuracy, we have developed a method termed Duplex Sequencing. This approach greatly reduces errors by independently tagging and sequencing each of the two strands of a DNA duplex. As the two strands are complementary, true mutations are found at the same position in both strands. In contrast, PCR or sequencing errors result in mutations in only one strand and can thus be discounted as technical error. We determine that Duplex Sequencing has a theoretical background error rate of less than one artifactual mutation per billion nucleotides sequenced. In addition, we establish that detection of mutations present in only one of the two strands of duplex DNA can be used to identify sites of DNA damage. We apply the method to directly assess the frequency and pattern of random mutations in mitochondrial DNA from human cells.
| S-EPMC3437896 | biostudies-other
Project description:Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.
| S-EPMC4917884 | biostudies-literature