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Biomedical subjects

Sven Cichon

Publications and source records attributed to Sven Cichon.

10 recordsLinked to original sources
PubMed2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Brain↗
PubMed2002

Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder.

Irregularities of dopaminergic and serotonergic neurotransmission have been implicated in a variety of neuropsychiatric disorders. DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, is an enzyme involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered as a candidate gene for affective disorders. Recently, two novel variants were reported in the DDC gene: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Subsequently, an association case-control study including 112 English patients and 80 Danish patients with bipolar affective disorder (BPAD) revealed a significant association with the 1-bp deletion. This finding prompted us to analyze whether this effect was also present in a larger and ethnically homogeneous sample of 228 unrelated German patients with BPAD (208 patients with BP I disorder, 20 patients with BP II disorder), 183 unrelated patients with unipolar affective disorder (UPAD), and 234 healthy control subjects. For both BPAD and UPAD we could not detect a genetic association with either variant. Thus, our results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders.

Adult↗
PubMed2002

Can long-range microsatellite data be used to predict short-range linkage disequilibrium?

The distribution of linkage disequilibrium (LD) across the genome is highly complex. Little is known about the relationship between long-range and short-range LD in a genomic region. We assessed whether a dense set of microsatellite data could be used to predict short-range LD in family samples. We analyzed intermarker LD in data derived from chromosomal regions 18q22 and 10q25-26, densely genotyped with microsatellite markers. The pattern of LD was highly heterogeneous within and between both chromosomal regions. On 10q25-26, very little LD was detected. On 18q22, where marker density was higher, many marker pairs were in LD. We modeled the decay of LD over distance in this region. A classical model accounted for most of the relationship between LD and distance (R (2)=63%). We used this model to predict the proportion of markers expected to show useful levels of LD at short distances. This prediction agreed with estimates based on single-nucleotide polymorphism (SNP) marker genotypes in the region. Both microsatellite and SNP data predict that about 80% of marker pairs would display levels of LD that are useful for association studies at distances of up to 15 kb in this region. These projections also agree with levels of LD directly measured in a 10 kb set of SNP genotypes generated in a nearby region of finished sequence. Our results suggest that existing sets of microsatellite data, if sufficiently dense, may be used to develop good initial estimates of the density of additional markers needed to screen a region for disease alleles by association analysis.

Chromosome Mapping↗
PubMed2002

Association between a polymorphism in the pseudoautosomal X-linked gene SYBL1 and bipolar affective disorder.

In the past decade, several chromosomal regions have been analyzed for linkage with bipolar affective disorder (BPAD). There have been conflicting results regarding the involvement of X-chromosomal regions in harboring susceptibility genes for BPAD. Recently, a new candidate gene (SYBL1) for BPAD has been described on Xq28. SYBL1, which maps to the Xq pseudoautosomal region (PAR), encodes a member of the synaptobrevin family of proteins involved in synaptic vesicle docking, exocytosis, and membrane transport. A subsequent case-control association study, including 110 US-American patients with BPAD and 119 unrelated controls, investigated a potential etiological role of a novel polymorphism (G-->C transversion) in a regulatory region of the SYBL1 gene. In this analysis, the C allele showed a statistical trend to be more frequent in males with BPAD than in respective controls (P=0.06). This finding prompted us to verify whether a similar effect was also present in a larger German sample of 164 unrelated patients with BPAD (148 patients with BP I disorder, 16 patients with BP II disorder) and 267 controls. We observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls (P=0.017). Thus, our data strengthen the role of the SYBL1 gene as a candidate gene for BPAD.

Adult↗
PubMed2002

Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization.

Imbalances in glutamatergic function have been implicated in the pathogenesis of neuropsychiatric disorders. Consequently, glutamate receptors genes are promising candidates in search of susceptibility genes for these disorders. In the present study, we report the chromosomal sublocalization and genomic organization of the human metabotropic glutamate receptor 2 gene (GRM2). Using monochromosomal hybrid cell lines of NIGMS Mapping Panel 2 (Coriell Cell Repository), the GRM2 gene was localized to human chromosome 3, confirming previously reported localization. In addition, using the radiation hybrid panel RH3 (Research Genetics), we sublocalized the GRM2 gene to chromosomal region 3p21.1-p21.2. The genomic organization of the GRM2 gene was established using a premade library of adaptor-ligated, human-specific genomic DNA fragments. The gene consists of 5 exons, with sizes ranging from 74 to 1,076 bp.

Chromosome Mapping↗
PubMed2002

Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population.

In the present study, we sought to identify genetic variation in the metabotropic glutamate receptor 3 (GRM3) gene, which has been mapped to chromosome 7q21.1-q21.2 [Scherer et al., 1996] and might contribute to genetic predisposition to schizophrenia and/or bipolar affective disorder. Using single-strand conformation analysis (SSCA), we screened the complete coding sequence as well as adjacent splice sites of the GRM3 gene in a sample of 46 bipolar affective and 46 schizophrenic patients. We detected three sequence variants: a rare C/T substitution at nucleotide position +885 (T209T), a C/T substitution at nucleotide position +2130 (Y624Y), and a more common C/T substitution at nucleotide position +1131 (A291A). The occurrence of the +1131C/T variant was investigated in a sample of bipolar affective patients (n=283), schizophrenic patients (n=265), and ethnically matched controls (n=227). We observed a significant overrepresentation of the +1131T allele in schizophrenic patients when compared to controls (P=0.0022). This finding was followed up in an independent sample of schizophrenic patients (n=288) and controls (n=162) and 128 schizophrenic trios but could not be confirmed. It is therefore unlikely that this variant plays a major role in predisposing to schizophrenia and/or bipolar affective disorder at least in the German population.

Bipolar Disorder↗