Patient samples used for mapping complex human disease genes are unlikely to be representative of the phenotype spectrum of the respective population as a whole. On the other hand, most ongoing prospective studies are probably too small for evaluating polygenic disease markers.
Precise estimates of population-specific genotypic risks can be obtained efficiently through the complete ascertainment of patients in a geographically confined area. The PopGen project uses the most northern part of Germany as a target region for such a pursuit.
PopGen currently pursues recruitment, sampling and processing activities in close collaboration with a multitude of clinical partners, covering cardiovascular, neuropsychiatric and environmental diseases.
PopGen has successfully established itself as a large-scale genetic epidemiological project of international recognition.
"Control cohort microarray data include 1,287 unrelated European control subjects from the Study of Addiction: Genetics and Environment cohort (SAGE)
 genotyped with Illumina Human 1 M-single BeadChip arrays, 1,123 Northern Europeans from the German PopGen project (POPGEN)
 genotyped on the Affymetrix 6.0 SNP array (Affymetrix, Santa Clara, CA, USA), 1,234 individuals of European decent from the Ottawa River Valley (OHI)
 genotyped on the Affymetrix 6.0 SNP array, 1,320 European control subjects routinely seen at primary care and well-child clinic practices within the Children's Hospital of Philadelphia (CHOP) Health Care
 genotyped with Illumina 550 K BeadChip, 435 unrelated European control subjects from the Ontario Colorectal Cancer Case-Control study (OC)
 genotyped with the Illumina 1 M single array and 1,240 European controls from the NHGR-CIDR Visceral Adiposity Study
 genotyped on Illumina 1 M-duo BeadChip arrays. For all these control samples (except for the CHOP samples, for which the CNV data are available at
http://cnv.chop.edu), the heterozygous state of exonic CTNNA3 deletions has been determined by inspecting the genotypes and/or plotting B allele freq and log R ratios for each region. "
[Show abstract][Hide abstract] ABSTRACT: Background
Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution.
We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse.
The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development.
The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
"Recent genome-wide association studies (GWASs) showed that LDLR gene mutations were significantly associated with the abnormal blood lipid levels and CHD  . Among the LDLR polymorphisms, rs2228671 was associated with LDL-C levels and CHD in German and British populations     . However, discrepancies were also shown in the association of LDLR rs2228671 with CHD in Italians and Germans  . "
[Show abstract][Hide abstract] ABSTRACT: Low density lipoprotein receptor (LDLR) can regulate cholesterol metabolism by removing the excess low density lipoprotein cholesterol (LDL-C) in blood. Since cholesterol metabolism is often disrupted in coronary heart disease (CHD), LDLR as a candidate gene of CHD has been intensively studied. The goal of our study is to evaluate the overall contribution of LDLR rs2228671 polymorphism to the risk of CHD by combining the genotyping data from multiple case-control studies. Our meta-analysis is involved with 8 case-control studies among 7588 cases and 9711 controls to test the association between LDLR rs2228671 polymorphism and CHD. In addition, we performed a case-control study of LDLR rs2228671 polymorphism with the risk of CHD in Chinese population. Our meta-analysis showed that rs2228671-T allele was significantly associated with a reduced risk of CHD (P = 0.0005, odds ratio (OR) = 0.83, and 95% confidence interval (95% CI) = 0.75-0.92). However, rs2228671-T allele frequency was rare (1%) and was not associated with CHD in Han Chinese (P = 0.49), suggesting an ethnic difference of LDLR rs2228671 polymorphism. Meta-analysis has established rs2228671 as a protective factor of CHD in Europeans. The lack of association in Chinese reflects an ethnic difference of this genetic variant between Chinese and European populations.
BioMed Research International 05/2014; 2014:564940. DOI:10.1155/2014/564940 · 3.17 Impact Factor
"FISH analysis was performed using fosmid G248P83477D10 or CTD-2314 N10 bacterial artificial chromosome. We investigated the frequency of deletions affecting CHD2 in high-resolution CNV data from among 13 control cohorts comprising a total of 26,826 individuals [10,14-26]. "
[Show abstract][Hide abstract] ABSTRACT: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.
We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.
Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.
The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.
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