Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Event Abstract Back to Event Polygenic scores from the MiR137 pathway explain variability in cognitive performance in patients with schizophrenia and controls. Donna Cosgrove1*, Derek Morris1, Ric Anney2, April Hargreaves2, Psychiatric Genomics Consortium1, Michael Gill2, Aiden Corvin2 and Gary Donohoe1 1 The Cognitive Genetics & Cognitive Therapy Group, Depts. of Psychology and Biochemistry, National University of Ireland Galway, Ireland 2 Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Ireland Introduction Genome-wide association studies have identified rs1622579, a common variant located within an intronic region of MiR137, as a risk variant for schizophrenia. MiR137 has a hypothesized role in neural cell proliferation, migration and maturation. Cognitively, this variant is associated with deficits in verbal episodic memory, and altered fronto-amygdala connectivity. As MiR137 interacts with several other genome wide associated variants (e.g. ZNF804A, TCF4, CACNA1C, CSMD1 and WBP1L), we tested whether these cognitive effects were associated with polygenic risk in a set of identified downstream targets of MiR137. Methodology Polygene scores were calculated by (1) selecting all identified downstream genetic targets of MiR137 (Hill et al., 2014); (2) selecting risk SNPs within each of these genes based on risk estimates from the Psychiatric Genomics Consortium (Ripke et al., 2011), and (3) ascribing a polygenic risk score to each participant based on the total number of risk alleles they carried. To define risk, we used 3 arbitrary p-value thresholds (p < 10-5, p < 0.05, and p < 0.5) from the PGC1 case-control analysis. To estimate these polygene effects on cognitive deficits associated with SZ (IQ, episodic and working memory, attention control, and theory of mind) linear regression analyses was performed, with age and gender entered as variables of no interest. We carried out three separate analyses: all cases and controls (n=586), patients with a broad diagnosis of psychosis including non-schizophrenia psychosis (n=489) and patients with schizophrenia and schizoaffective disorder (n=379). Results MiR137 polygenic risk scores were significantly higher in the broad and narrow diagnosis groups compared to the controls (F(2,1081) =5.52, p<0.01). Poorer performance on measures of IQ, memory, and attention were each found to be associated with higher MiR137 polygene scores thresholded at p=0.05, including paired associated learning (p<0.001); faces, letter-number sequencing (LNS) sustained attention to reaction time (SART) (p<0.01); full-scale IQ, logical memory (LM) and spatial working memory (SWM) (p<0.05). The amount of variance explained on the measures varied between 1% and 2.6% Discussion These data support a modest but significant influence of this MiR137 'pathway' on cognition, across multiple measures of cognition. These widespread cognitive effects are consistent with MiR137’s previously described role in brain development. Greater variance was explained when all cases and controls were included, rather than considering narrow, broad, and controls separately. Extending on previous findings, MiR137's effects on cognition were significantly more apparent when considered in combination with the other risk variants with which it interacts rather than when the rs1622579 risk variant was considered in isolation. References Hill, M. J., Donocik, J. G., Nuamah, R. A., Mein, C. A., Sainz-Fuertes, R., & Bray, N. J. (2014). Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells. Schizophr Res, 153(1-3), 225-230. Ripke, S., Sanders, A., Kendler, K., Levinson, D., Sklar, P., & Holmans, P. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature genetics, 43(10), 969-976. Keywords: miR137, Cognition, Schizophrenia, polygene, risk variant Conference: Neuroscience Ireland Young Neuroscientists Symposium 2014 , Dublin, Ireland, 20 Sep - 20 Sep, 2014. Presentation Type: Poster Presentation Topic: Early Career Neuroscience Citation: Cosgrove D, Morris D, Anney R, Hargreaves A, Genomics Consortium P, Gill M, Corvin A and Donohoe G (2014). Polygenic scores from the MiR137 pathway explain variability in cognitive performance in patients with schizophrenia and controls.. Front. Neurosci. Conference Abstract: Neuroscience Ireland Young Neuroscientists Symposium 2014 . doi: 10.3389/conf.fnins.2014.87.00013 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Sep 2014; Published Online: 10 Sep 2014. * Correspondence: Miss. Donna Cosgrove, The Cognitive Genetics & Cognitive Therapy Group, Depts. of Psychology and Biochemistry, National University of Ireland Galway, Galway, Ireland, donna.cosgrove@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Donna Cosgrove Derek Morris Ric Anney April Hargreaves Psychiatric Genomics Consortium Michael Gill Aiden Corvin Gary Donohoe Google Donna Cosgrove Derek Morris Ric Anney April Hargreaves Psychiatric Genomics Consortium Michael Gill Aiden Corvin Gary Donohoe Google Scholar Donna Cosgrove Derek Morris Ric Anney April Hargreaves Psychiatric Genomics Consortium Michael Gill Aiden Corvin Gary Donohoe PubMed Donna Cosgrove Derek Morris Ric Anney April Hargreaves Psychiatric Genomics Consortium Michael Gill Aiden Corvin Gary Donohoe Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Chinese-speaking older adults usually do not perceive a hearing problem until audiometric thresholds exceed 45 dB HL, and the audiometric thresholds of the average hearing-aid (HA) user often exceed 60 dB HL. The purpose of this study was to examine the relationships between cognitive and hearing functions (measured as audiometric or speech reception thresholds) in older Chinese adults with HAs and with untreated hearing loss (HL). Participants were 49 Chinese older adults who used HAs and had moderate to severe HL (HA group), and 46 older Chinese who had mild to moderately severe HL but did not use HAs (untreated; or UT group). Multiple linear regression analysis was employed to evaluate how well age, education level, audiometric thresholds, and speech perception in noise were related to performance on general cognitive function, working memory, executive function, attention, and verbal learning tests. Results showed that speech perception in noise alone accounted for 13–25% of the variance in general cognitive function, working memory, and executive function in the UT group, and 9–21% of the variance in general cognitive function and verbal learning in the HA group (i.e., medium effect sizes). Audiometric thresholds did not explain any proportion of the variance in cognitive functioning in the HA or UT group. Thus, speech perception in noise accounts for more variance in cognitive performance than audiometric thresholds, and is significantly associated with different cognitive functions in older Chinese adults with HAs and with untreated HL.

BackgroundAging population is rapidly growing in India, with the majority of the older adult population residing in rural regions. Studies globally show a higher prevalence of cognitive impairment in rural regions than urban. With the lack of research on aging in India, there is an urgent need to evaluate the cognitive health of older adults in India to allow for their care needs to be met appropriately and promote healthy aging.MethodThis study used data from Harmonized Longitudinal Aging Study of India, Diagnostic Assessment of Dementia (LASI DAD), which was developed by the Gateway to Global Aging Data. The sample size was nationally representative (n = 4096) of older adults aged 60 years and above in India (urban community = 1561, rural village = 2535). Given the heterogeneity of the population, adapted cognitive instruments were used. This study assessed if geographical residency (urban vs. rural) of older adults influenced their cognitive performance above and beyond demographic factors (i.e., age and gender) and education using a hierarchical regression in SPSS.Result18% of the variance in cognitive performance was accounted for by age and gender. 37% of the variance in cognitive performance was accounted for by the addition of education. Finally, geographic residency accounted for 1.2% of the variance in cognitive performance of older adults. Older adults living in rural villages had statistically significantly lower cognitive performance than older adults living in urban communities (B = ‐.218, p &lt; 0.01). Women’s cognitive performance was lower than men’s (B = ‐.229, p &lt;0.01).ConclusionThe geographic residency only accounted for a small proportion of variance in the cognitive performance of older adults in India. The majority of the disparity was accounted for by education, with older adults with higher education performing better. Despite that, older adults living in rural villages performed worse on cognitive measures than older adults living in urban communities. Older women performed worse than men. The contribution of factors such as depression, socioeconomic status, and cardiovascular health to the cognitive health of older adults in India should be explored further.

Genome wide association studies (GWAS) conducted primarily in European Ancestry (EA) have identified hundreds of single nucleotide polymorphisms (SNPs) that are associated with general cognitive function. The association between these SNPs and cognitive function has not yet been evaluated in South Asians yet, either individually or in polygenic risk scores (PRS) which aggregate the effects from many SNPs across the genome. The goal of this study was to investigate whether SNPs identified in EA GWAS, either individually or as a PRS, were associated with a general cognitive factor and the Hindi version of the Mini-Mental State Examination (HMSE) score in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). Participants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. We used linear models to assess the association between 130 top SNPs from the EA GWAS (p<5e-08) and both measures of cognitive function after controlling for age, gender, and population structure. We also evaluated the association between PRSs using the top GWAS SNPs and the cognitive measures using the same models. Finally, we estimated the variation in cognitive function explained by the cognitive function PRS, Alzheimer's disease (AD) PRSs, and/or APOE e2 and e4 genotypes individually or simultaneously. Preliminary analyses showed that none of the GWAS SNPs were significantly associated either of the cognitive measures after multiple testing correction. The PRS, however, was significantly associated with the general cognitive factor and HMSE score (p<0.025). The PRS explained 0.40% and 0.59% of the variance in the general cognitive factor and HMSE score, and explained 1.50% and 1.85% of the variance when coupled with AD PRSs and APOE genotypes. SNPs identified for cognitive function in EA GWAS may not be as strongly associated in South Asians. However, the genetic risk score for both general cognitive function and AD contribute additively to cognitive function in LASI-DAD participants. Future large scale GWAS of general cognitive function and AD are needed to identify specific risk variants for cognition in South Asians.

We investigated the association of the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) and an Alzheimer disease (AD) genetic risk score (GRS) with cognitive performance. The ANU-ADRI (composed of 12 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modeling was used to evaluate the association of the ANU-ADRI and GRS with: (1) general cognitive ability (g), (2) dementia-related variance in cognitive performance (δ), and (3) verbal ability (VA), episodic memory (EM), executive function (EF), and processing speed (PS). A worse ANU-ADRI score was associated with poorer performance in "g" [β (SE)=-0.40 (0.02), P<0.001], δ [-0.40 (0.04), P<0.001], and each cognitive domain [VA=-0.29 (0.04), P<0.001; EM=-0.34 (0.03), P<0.001; EF=-0.38 (0.03), P<0.001; and PS=-0.40 (0.03), P<0.001]. A worse GRS was associated with poorer performance in δ [-0.08 (0.03), P=0.041] and EM [-0.10 (0.03), P=0.035]. The ANU-ADRI was broadly associated with worse cognitive performance, including general ability and dementia severity, validating its further use in early dementia risk assessment.

Studies in animals and humans have suggested that exercise training can positively affect cognitive abilities. Lower performance in cognition is associated with higher intra-individual variability on repeated cognitive tests. PURPOSE: To investigate whether a correlation exists between physical fitness and intra-individual variability in cognitive performance in older subjects. METHODS: 8 men and 7 women participated and completed three test sessions, at the same time of the day, following the same protocol, within fourteen days. One session consisted of (i) assessment of the physical fitness (maximal voluntary contraction of the quadriceps muscles, gait velocity, and a cycling test to estimate the maximal oxygen uptake (VO2-max)) and (ii) assessment of the cognitive task performance (Trail Making Test and Stroop colour word Test). RESULTS: Physical fitness was not correlated to intra-individual variability in cognitive performance. Correlations for cognitive tests variability with muscle strength are r=0.28; P=0.33, with gait velocity r=−0.06, P=0.8 and with estimated maximal oxygen uptake r=0.5, P=0.12. Due to a learning effect over the three sessions (ANOVA) it is questionable if the standard deviation and coefficient of variation calculated for cognitive tests represent intra-individual variability. CONCLUSION: This study did not show a correlation between physical fitness and intra-individual variability in cognitive task performance. A larger population and avoidance of a learning effect in testing should be applied to answer the question more properly.

The evolution of genetic sex determination is often accompanied by degradation of the sex-limited chromosome. Male heterogametic systems have evolved convergent, epigenetic mechanisms restoring the resulting imbalance in gene dosage between diploid autosomes (AA) and the hemizygous sex chromosome (X). Female heterogametic systems (AAf Zf, AAm ZZm) tend to only show partial dosage compensation (0.5 < Zf:AAf < 1) and dosage balance (0.5<Zf:ZZm<1). The underlying mechanism remains largely elusive. Here, we quantified gene expression for a total of 15 male and female Eurasian crows (Corvus (corone) spp.) raised under common garden conditions. In addition, we characterized aspects of the regulatory epigenetic landscape quantifying chromatin accessibility (ATAC-seq) and 5mC methylation profiles. Partial dosage balance and compensation was due to female upregulation of Z-linked genes which covaried significantly with increased chromatin accessibility of the female Z chromosome. 5mC methylation was tissue and sex chromosome-specific, but unrelated to dosage. With the exception of the pseudo-autosomal region (PAR), female upregulation of gene expression was evenly spread across the Z chromosome without evidence for regional centers of epigenetic regulation, as has, for example, been suggested for the male hypermethylated region (MHM) in chicken. Our results suggest that partial dosage balance and compensation in female heterogametic systems are tightly linked to chromosome-wide, epigenetic control of the female Z chromosome mediated by differential chromatin accessibility.

The evolution of genetic sex determination is often accompanied by degradation of the sex-limited chromosome. Male heterogametic systems have evolved convergent, epigenetic mechanisms restoring the resulting imbalance in gene dosage between diploid autosomes (AA) and the hemizygous sex chromosome (X). Female heterogametic systems (AAf Zf, AAm ZZm) tend to only show partial dosage compensation (0.5 < Zf:AAf < 1) and dosage balance (0.5<Zf:ZZm<1). The underlying mechanism remains largely elusive. Here, we quantified gene expression for a total of 15 male and female Eurasian crows (Corvus (corone) spp.) raised under common garden conditions. In addition, we characterized aspects of the regulatory epigenetic landscape quantifying chromatin accessibility (ATAC-seq) and 5mC methylation profiles. Partial dosage balance and compensation was due to female upregulation of Z-linked genes which covaried significantly with increased chromatin accessibility of the female Z chromosome. 5mC methylation was tissue and sex chromosome-specific, but unrelated to dosage. With the exception of the pseudo-autosomal region (PAR), female upregulation of gene expression was evenly spread across the Z chromosome without evidence for regional centers of epigenetic regulation, as has, for example, been suggested for the male hypermethylated region (MHM) in chicken. Our results suggest that partial dosage balance and compensation in female heterogametic systems are tightly linked to chromosome-wide, epigenetic control of the female Z chromosome mediated by differential chromatin accessibility.

Investigating the Genetic Architecture of Non-Cognitive Skills Using Gwas-by-Subtraction

The First Baby Born After Polygenic Embryo Screening

Cognitive deficits in multiple sclerosis (MS) are common and correlate with contemporary MRI brain abnormalities, particularly atrophy, but the ability of imaging early in the disease to predict later cognitive impairment remains to be determined. Thirty relapsing—remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed neuropsychologically five years later. Imaging parameters accounting for significant variance in cognitive performance were identified using multiple regressions, once confounding variables were controlled. Patients performed significantly worse than expected on tests of attention/speed of information processing and half of them had experienced some decline in IQ in relation to premorbid estimates. The rate of global brain atrophy in the first year of the study accounted for significant variance in the overall cognitive performance, and in memory and attention/speed of information processing. Poor performance on attention tests was associated with high T1-weighted lesion volume and reduced magnetization transfer ratio (MTR) in normal-appearing white matter (NAWM). These results suggest that neuroaxonal loss was identified early in the disease, and its rate of progression, predicted cognitive impairment later in the disease. Neuroaxonal loss is likely to affect commissural and association fibres that subserve the cognitive processes impaired in MS. Multiple Sclerosis 2008; 14: 197—204. http://msj.sagepub.com

The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled ‘cognitively impaired’ subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory–Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1–42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1–42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.

Polygenic prediction has yet to make a major clinical breakthrough in precision medicine and psychiatry, where the application of polygenic risk scores is expected to improve clinical decision-making. Most widely used approaches for estimating polygenic risk scores are based on summary statistics from external large-scale genome-wide association studies, which rely on assumptions of matching data distributions. This may hinder the impact of polygenic risk scores in modern diverse populations due to small differences in genetic architectures. Reference-free estimators of polygenic scores are instead based on genomic best linear unbiased predictions and model the population of interest directly. We introduce a framework, named hapla, with a novel algorithm for clustering haplotypes in phased genotype data to estimate heritability and perform reference-free polygenic prediction in complex traits. We utilize inferred haplotype clusters to compute accurate heritability estimates and polygenic scores in a simulation study and the iPSYCH2012 case-cohort for depression disorders and schizophrenia. We demonstrate that our haplotype-based approach robustly outperforms standard genotype-based approaches, which can help pave the way for polygenic risk scores in the future of precision medicine and psychiatry.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used Genomic Structural Equation Modeling and prior genome-wide association studies (GWAS) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability.We identified 157 genome-wide significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Non-cognitive genetics were enriched in the same brain tissues and cell types as cognitive performance but showed different associations with gray-matter brain volumes. Non-cognitive genetics were further distinguished by associations with personality traits, less risky behavior,and increased risk for certain psychiatric disorders.For socioeconomic success and longevity, non-cognitive and cognitive-performance genetics demonstrated similar-magnitude associations. By conducting a GWAS of a phenotype that was not directly measured, we offer a first view of genetic architecture of non-cognitive skills influencing educational success.

Genetic association studies routinely require many thousands of participants to achieve sufficient power, yet accumulation of large well-assessed samples is costly. We describe here an effort to efficiently measure cognitive ability and personality in an online genetic study, Genes for Good. We report on the first 21,550 participants with relevant phenotypic data, 7,458 of whom have been genotyped genome-wide. Measures of crystallized and fluid intelligence reflected a two-dimensional latent ability space, with items demonstrating adequate item-level characteristics. The Big Five Inventory questionnaire revealed the expected five-factor model of personality. Cognitive measures predicted educational attainment over and above personality characteristics, as expected. We found that a genome-wide polygenic score of educational attainment predicted educational level, accounting for 4%, 4%, and 2.7% of the variance in educational attainment, verbal reasoning, and spatial reasoning, respectively. In summary, the online cognitive measures in Genes for Good appear to perform adequately and demonstrate expected associations with personality, education, and an education-based polygenic score. Results indicate that online cognitive assessment is one avenue to accumulate large samples of individuals for genetic research of cognitive ability.