22 research outputs found
Genetic and Phenotypic Features of Schizophrenia in the UK Biobank
IMPORTANCE Large-scale biobanks provide important opportunities for mental health
research, but selection biases raise questions regarding the comparability of individuals
with those in clinical research settings.
OBJECTIVE To compare the genetic liability to psychiatric disorders in individuals with
schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium
(PGC) and to compare genetic liability and phenotypic features with participants recruited
from clinical settings.
DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included participants from
the population-based UK Biobank and schizophrenia samples recruited from clinical settings
(CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected
between January 1993 and July 2021. Data analysis was conducted between July 2021
and June 2023.
MAIN OUTCOMES AND MEASURES A genome-wide association study of UK Biobank
schizophrenia case-control status was conducted, and the results were compared with
those from the PGC via genetic correlations. To test for differences with the clinical samples,
polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression,
and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using
pairwise logistic regressions. The proportions of individuals with copy number variants
associated with schizophrenia were compared using Firth logistic regression.
RESULTS The sample of 517 375 participants included 1438 UK Biobank participants with
schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank
controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia
research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to
schizophrenia in UK Biobank was highly correlated with the latest genome-wide association
study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns
of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the
variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with
schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained
samples and significantly lower rates of schizophrenia-associated copy number variants than
the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational
attainment and employment rates than the clinically ascertained schizophrenia samples,
lower rates of smoking, and a later age of onset of psychosis.
CONCLUSIONS AND RELEVANCE Individuals with schizophrenia in the UK Biobank, and likely
other volunteer-based biobanks, represent those less severely affected. Their inclusion in
wider studies should enhance the representation of the full spectrum of illness severity
Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia
Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy
Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants
Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis
Regions of the genome that affect agronomic performance in two-row barley
Quantitative trait locus (QTL) main effects and QTL by environment (QTL × E) interactions for seven agronomic traits (grain yield, days to heading, days to maturity, plant height, lodging severity, kernel weight, and test weight) were investigated in a two-row barley (Hordeum vulgare L.) cross, Harrington/TR306. A 127-point base map was constructed from markers (mostly RFLP) scored in 146 random double-haploid (DH) lines from the Harrington/TR306 cross. Field experiments involving the two parents and 145 random DH lines were grown in 1992 and/or 1993 at 17 locations in North America. Analysis of QTL was based on simple and composite interval mapping. Primary QTL were declared at positions where both methods gave evidence for QTL. The number of primary QTL ranged from three to six per trait, collectively explaining 34 to 52% of the genetic variance. None of these primary QTL showed major effects, but many showed effects that were consistent across environments. The addition of secondary QTL gave models that explained 39 to 80% of the genetic variance. The QTL were dispersed throughout the barley genome and some were detected in regions where QTL have been found in previous studies. Eight chromosome regions contained pleiotropic loci and/or linked clusters of loci that affected multiple traits. One region on chromosome 7 affected all traits except days to heading. This study was an intensive effort to evaluate QTL in a narrow-base population grown in a large set of environments. The results reveal the types and distributions of QTL effects manipulated by plant breeders and provide opportunities for future testing of marker-assisted selection
HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects
Age at first birth in women is genetically associated with increased risk of schizophrenia
Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe
Mapping of disease resistance loci in barley based on visual assessment of naturally occurring symptoms
Using field-scored data of disease severity under natural infestation, we mapped loci affecting resistance to powdery mildew (Blumeria graminis DC f. sp. hordei Ém. Marchal), leaf rust (Puccinia hordei Otth.), stem rust (Puccinia graminis f. sp. tritici Eriks. & E. Henn.), scald [Rhynchosporium secalis (Oudem.) J.J. Davis], and net blotch (Pyrenophora teres Drechs.). The mapping population included parents and doubled-haploid progeny of the two-row barley cross Harrington/TR306. Resistance was affected by two to five loci, explaining 8 to 45% of the phenotypic variance, per disease. All chromosomes, except chromosome 5 (1H), contained regions with at least one disease resistance locus. One region on chromosome 4 (4H) contributed to resistance to stem rust, scald, and net blotch. This region has previously been reported to affect days to heading and maturity. Two known resistance genes in the population, Rpgl and M1g, were mapped to within 3 centimorgans (cM) of their previously estimated genomic locations by simple interval mapping of the field-scored data. This indicates that the genomic positions of disease resistance genes can be estimated accurately with simple interval mapping, even on the basis of field-scored data
Synaptic protein DLG2 controls neurogenic transcriptional programs disrupted in schizophrenia and related disorders
Genetic studies robustly implicate perturbation of DLG2-scaffolded mature postsynaptic signalling complexes in schizophrenia. Here we study in vitro cortical differentiation of DLG2-/- human embryonic stem cells via integrated phenotypic, gene expression and disease genetic analyses. This uncovers a developmental role for DLG2 in the regulation of neural stem cell proliferation and adhesion, and the activation of transcriptional programs during early excitatory corticoneurogenesis. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and causes marked deficits in neuronal migration, morphology and active properties. Genetic risk factors for neuropsychiatric and neurodevelopmental disorders converge on these neurogenic programs, each disorder displaying a distinct pattern of enrichment. These data unveil an intimate link between neurodevelopmental and mature signalling deficits contributing to disease - suggesting a dual role for known synaptic risk genes - and reveal a common pathophysiological framework for studying the neurodevelopmental origins of Mendelian and genetically complex mental disorders