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How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
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Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Esquizofrenia/metabolismo , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismo , Animales , Dendritas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Análisis de la Célula Individual , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12RESUMEN
PURPOSE: Women diagnosed with non-affective psychosis have a lower general fertility rate (GFR) and age-specific fertility rate (ASFR) than women in the general population. Contemporary data on GFR in this group remain limited, despite substantive changes in prescribing and management. We calculated contemporary estimates of the GFR and ASFR for women diagnosed with non-affective psychosis compared with the general population of women without this diagnosis. METHODS: A population-based design combined routinely collected historical maternity and psychiatric data from two representative areas of Scotland. Women were included from the NHS Grampian or Greater Glasgow and Clyde areas and were aged 15-44 between 2005 and 2013 inclusive. The 'exposed' group had a diagnosis of non-affective psychosis (ICD-10 F20-F29) and was compared to the general population of 'unexposed' women in the same geographical areas. RESULTS: Annual GFR between 2005 and 2013 for women with non-affective psychosis varied from 9.6 to 21.3 live births/1000 women per year in the exposed cohort and 52.7 to 57.8 live births/1000 women per year in the unexposed cohort, a rate ratio (RR) of 0.28 [p < 0.001; 95% CI (0.24, 0.32)]. ASFR for all 5-year age groups was lower in the exposed cohort than amongst unexposed women. CONCLUSION: We highlight continued low fertility rates in women with a diagnosis of non-affective psychosis, despite widespread availability of prolactin-sparing atypical antipsychotics. Accurate estimation of fertility rates remains crucial in developing needs-matched perinatal care for these women. Methodological improvements using routine datasets to investigate perinatal mental health are also urgently needed.
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Antipsicóticos , Trastornos Psicóticos , Humanos , Femenino , Embarazo , Tasa de Natalidad , Antipsicóticos/uso terapéutico , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/tratamiento farmacológico , Escocia/epidemiologíaRESUMEN
To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
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Ancirinas/genética , Trastorno Bipolar/genética , Canales de Calcio Tipo L/genética , Estudio de Asociación del Genoma Completo , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 15 , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Polimorfismo de Nucleótido SimpleRESUMEN
Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
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Trastorno Bipolar/genética , Duplicación Cromosómica , Proteínas del Tejido Nervioso/metabolismo , Trastornos Psicóticos/genética , Esquizofrenia/genética , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Trastorno Bipolar/patología , Estudios de Casos y Controles , Puntos de Rotura del Cromosoma , Variaciones en el Número de Copia de ADN , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Masculino , Plasticidad Neuronal , Trastornos Psicóticos/patología , Esquizofrenia/patología , Población Blanca/genéticaRESUMEN
Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (Pâ=â0.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.
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Variaciones en el Número de Copia de ADN/genética , Neuritas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Esquizofrenia/genética , Animales , Movimiento Celular/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Neuritas/patología , Neuronas/metabolismo , Neuronas/patología , Esquizofrenia/etiología , Esquizofrenia/patología , Eliminación de SecuenciaRESUMEN
Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Herencia Multifactorial/genética , Esquizofrenia/genética , Trastorno Bipolar/genética , Estudios de Casos y Controles , Trastorno Depresivo Mayor/genética , Familia , Humanos , Patrón de Herencia/genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia. METHODS: The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure. RESULTS: In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10(-9) and 5.36×10(-9), respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring. CONCLUSIONS: Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia.
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Expresión Génica/fisiología , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiologicos de la Nutrición Prenatal , Inanición/fisiopatología , Animales , Metilación de ADN , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Epigénesis Genética , Femenino , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Análisis por Micromatrices , Fenotipo , Embarazo , Ratas Sprague-Dawley , EsquizofreniaRESUMEN
In the United States, more than 90% of hospitals still use only the traditional "spray and wipe" disinfection methods initiated over a century ago to protect patients from their environment; international adoption of new methods is even lower. Innovative approaches like whole room disinfection find an inhospitable reception in spite of clearly superior reductions in health care-acquired infections. Much of the resistance is due to a lack of true accountability for patient safety in hospital organizations and to perverse incentive structures in historical reimbursement policies. But all of that may change in the coming years as hospitals and doctors become more responsible for the health outcomes of their patients.
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Desinfección/instrumentación , Administración Hospitalaria , Cultura Organizacional , Infección Hospitalaria/prevención & control , Humanos , Administración de la SeguridadRESUMEN
Previous studies have demonstrated that the levels of IgG against neurotransmitter receptors are increased in patients with schizophrenia. Genome-wide association (GWA) studies of schizophrenia confirmed that 108 loci harbouring over 300 genes were associated with schizophrenia. Although the functional implications of genetic variants are unclear, theoretical functional alterations of these genes could be replicated by the presence of autoantibodies. This study examined the levels of plasma IgG antibodies against four neurotransmitter receptors, CHRM4, GRM3, CHRNA4 and CHRNA5, using an in-house ELISA in 247 patients with schizophrenia and 344 non-psychiatric controls. Four peptides were designed based on in silico analysis with computational prediction of HLA-DRB1 restricted and B-cell epitopes. The relationship between plasma IgG levels and psychiatric symptoms, as defined by the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), were examined. The results showed that the levels of plasma IgG against peptides derived from CHRM4 and CHRNA4 were significantly increased in patients with schizophrenia compared with control subjects, but there was no significant association of plasma IgG levels with any symptom domain or any specific symptoms. These preliminary results suggest that CHRM4 and CHRNA4 may be novel targets for autoantibody responses in schizophrenia, although the pathogenic relationship between increased serum autoantibody levels and schizophrenia symptoms remains unclear.
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Autoanticuerpos , Inmunoglobulina G , Receptores Colinérgicos , Esquizofrenia , Humanos , Esquizofrenia/sangre , Esquizofrenia/inmunología , Autoanticuerpos/sangre , Femenino , Masculino , Adulto , Persona de Mediana Edad , Inmunoglobulina G/sangre , Receptores Colinérgicos/inmunología , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1tr exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.
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Dopamina , Esquizofrenia , Ratones , Humanos , Animales , Dopamina/metabolismo , Esquizofrenia/metabolismo , Área Tegmental Ventral/metabolismo , Ratones Transgénicos , Corteza Prefrontal/metabolismo , Glucosa/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
BACKGROUND: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.
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Metilación de ADN , Esquizofrenia , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Envejecimiento/genética , Senescencia Celular , Epigénesis Genética , Esquizofrenia/genéticaRESUMEN
Copy number variants are small chromosomal deletions and duplications. When they alter the dose of genes critical for normal brain development and adult brain functioning they may cause severe disorders such as autism and schizophrenia. Numerous such loci have recently been identified. They are offering amazing leads for neuropsychiatric research.
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Variaciones en el Número de Copia de ADN/genética , Trastornos Mentales/genética , Psiquiatría , Adulto , Genoma Humano/genética , HumanosRESUMEN
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aß, is now known to be an antimicrobial peptide, and Aß deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
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Enfermedad de Alzheimer , Inmunosenescencia , Animales , Humanos , Ratones , Anciano , Inmunosenescencia/fisiología , Enfermedad de Alzheimer/genética , Autorrenovación de las Células , Envejecimiento , Mamíferos , HormonasRESUMEN
Autoantibodies targeting the central nervous system have been shown to induce psychiatric symptoms resembling schizophrenia. Concurrently, genetic studies have characterised a number of risk variants associated with schizophrenia although their functional implications are largely unknown. Any biological effects of functional variants on protein function may potentially be replicated by the presence of autoantibodies against such proteins. Recent research has demonstrated that the R1346H variant in the CACNA1I gene coding for the Cav 3.3 protein results in a synaptic reduction of Cav3.3 voltage gated calcium channels and, consequently, sleep spindles, which have been shown to correlate with several symptom domains in patients with schizophrenia. The present study measured plasma levels of IgG against two peptides derived from CACNA1I and CACNA1C, respectively, in patients with schizophrenia and healthy controls. The results demonstrated that increased anti-CACNA1I IgG levels were associated with schizophrenia but not associated with any symptom domain related to the reduction of sleep spindles. In contrast to previously published work indicating that inflammation may be a marker for a depressive phenotype, plasma levels of IgG against either CACNA1I or CACNA1C peptides were not associated with depressive symptoms, suggesting that anti-Cav3.3 autoantibodies may function independently of pro-inflammatory processes.
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Background: This study attempts to replicate in a Chinese population an earlier UK report that eye movement abnormalities can accurately distinguish schizophrenia (SCZ) cases from healthy controls (HCs). It also seeks to determine whether first-episode SCZ differ from chronic SCZ and whether these eye movement abnormalities are enriched in psychosis risk syndrome (PRS). Methods: The training set included 104 Chinese HC and 60 Chinese patients with SCZ, and the testing set included 20 SCZ patients and 20 HC from a UK cohort. An additional 16 individuals with PRS were also enrolled. Eye movements of all participants were recorded during free-viewing, smooth pursuit, and fixation stability tasks. Group differences in 55 performance measures were compared and a gradient-boosted decision tree model was built for predictive analyses. Results: Extensive eye-movement abnormalities were observed in patients with SCZ on almost all eye-movement tests. On almost all individual variables, first-episode patients showed no statistically significant differences compared with chronic patients. The classification model was able to discriminate patients from controls with an area under the curve of 0.87; the model also classified 88% of PRS individuals as SCZ-like. Conclusions: Our findings replicate and extend the UK results. The overall accuracy of the Chinese study is virtually identical to the UK findings. We conclude that eye-movement abnormalities appear early in the natural history of the disorder and can be considered as potential trait markers for SCZ diathesis.
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The discovery of 'high-risk' de novo copy number variants (CNVs) associated with neuropsychiatric disorders such as schizophrenia offers the opportunity to translate these findings into useful tools for clinical geneticists. However, this will require estimation of penetrance for these variants, which has not yet been properly considered. To facilitate this process, we estimated the penetrance of CNVs associated with schizophrenia, at 15q13.3, 1q21.1, 15q11.2, 17p12, 2p16.3, 16p13.1 and 16p11.2 with a novel Bayesian method applied to pooled data from published case-control studies. For these CNVs, penetrance for schizophrenia was between 2 and 7.4%, which contrasts with the much higher penetrance for schizophrenia of the 22q11.2 deletions found in velo-cardio-facial syndrome. The highest penetrance was for 15q13.3 deletion (6-9% in individual studies) and the lowest was for 15q11.2 (2%). CNVs confer much higher risk for schizophrenia than common variants, but their penetrance is substantially lower than Mendelian disorders or other syndromic conditions. Since these CNVs predispose to multiple disorders, including epilepsy, autism and intellectual impairment, penetrance estimates will also need to take into account diagnostic specificity, and their overall penetrance for any neuropsychiatric disorder is likely to be much higher. Thus, although CNVs are still far from being clinically useful or relevant to genetic counselling for specific disorders, their detection may hold an important clinical value in predicting negative developmental outcomes.
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Variaciones en el Número de Copia de ADN , Esquizofrenia/genética , Estudios de Casos y Controles , Deleción Cromosómica , Dosificación de Gen , HumanosRESUMEN
The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.
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Proteínas Adaptadoras Transductoras de Señales/genética , Esquizofrenia/genética , Proteínas Adaptadoras del Transporte Vesicular , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Población Blanca/genéticaRESUMEN
Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.
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Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/fisiología , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Secuencia de Aminoácidos , Trastorno Bipolar/genética , Estudios de Casos y Controles , Codón sin Sentido , Citogenética , Análisis Mutacional de ADN , Depresión/genética , Exones , Femenino , Ligamiento Genético , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Missense , Esquizofrenia/genética , Homología de Secuencia de AminoácidoRESUMEN
The Icelandic population has been sampled in many disease association studies, providing a strong motivation to understand the structure of this population and its ramifications for disease gene mapping. Previous work using 40 microsatellites showed that the Icelandic population is relatively homogeneous, but exhibits subtle population structure that can bias disease association statistics. Here, we show that regional geographic ancestries of individuals from Iceland can be distinguished using 292,289 autosomal single-nucleotide polymorphisms (SNPs). We further show that subpopulation differences are due to genetic drift since the settlement of Iceland 1100 years ago, and not to varying contributions from different ancestral populations. A consequence of the recent origin of Icelandic population structure is that allele frequency differences follow a null distribution devoid of outliers, so that the risk of false positive associations due to stratification is minimal. Our results highlight an important distinction between population differences attributable to recent drift and those arising from more ancient divergence, which has implications both for association studies and for efforts to detect natural selection using population differentiation.
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Variación Genética , Genética de Población , Frecuencia de los Genes , Enfermedades Genéticas Congénitas/genética , Humanos , Islandia , Polimorfismo de Nucleótido SimpleRESUMEN
We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.