M. Rietschel

Bio: M. Rietschel is an academic researcher from Heidelberg University. The author has contributed to research in topics: Schizophrenia & Genome-wide association study. The author has an hindex of 35, co-authored 106 publications receiving 3734 citations. Previous affiliations of M. Rietschel include University of Bonn.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Abstract: Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Genetic association of the human corticotropin releasing hormone receptor 1 ( CRHR1 ) with binge drinking and alcohol intake patterns in two independent samples

Abstract: Genetic association of the human corticotropin releasing hormone receptor 1 ( CRHR1 ) with binge drinking and alcohol intake patterns in two independent samples

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

Abstract: Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.

The neural basis of video gaming

Abstract: Video game playing is a frequent recreational activity. Previous studies have reported an involvement of dopamine-related ventral striatum. However, structural brain correlates of video game playing have not been investigated. On magnetic resonance imaging scans of 154 14-year-olds, we computed voxel-based morphometry to explore differences between frequent and infrequent video game players. Moreover, we assessed the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging and the Cambridge Gambling Task (CGT). We found higher left striatal grey matter volume when comparing frequent against infrequent video game players that was negatively correlated with deliberation time in CGT. Within the same region, we found an activity difference in MID task: frequent compared with infrequent video game players showed enhanced activity during feedback of loss compared with no loss. This activity was likewise negatively correlated with deliberation time. The association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity.

Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.

Abstract: The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with ‘early-onset’ (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case–control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Major depressive disorder

Abstract: Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

Abstract: Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.

Identification of common genetic risk variants for autism spectrum disorder

Abstract: Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.