PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships.
ABSTRACT 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.
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ABSTRACT: Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, `de novo` microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies. Copyright © 2015. Published by Elsevier Masson SAS.European journal of medical genetics. 01/2015;
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ABSTRACT: Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.The American Journal of Human Genetics 01/2015; 96(1):104-120. · 11.20 Impact Factor
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ABSTRACT: Background- Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. Methods and Results- In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case-control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1,448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN (PLG) (rs4252120, Ppooled=5.9x10-5, OR=1.27, 95% CI=1.3-1.4 [adjusted for smoking and sex]; 818 cases, 5,309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895 P=0.0016, OR=1.27 [95% CI=1.1-1.5]; 703 cases, 2.143 controls) and CAD (P=0.0003, OR=0.84 [95% CI=0.8-0.9]; N=4,117 cases, 5,824 controls). The study further provides evidence that in addition to PLG, the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3, are subjected to TGF-β regulation. Conclusions- PLG is the third known shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of TGF-β signaling. Key words: genetic association, coronary artery disease, periodontitis, plasminogen, TGF-βCirculation Cardiovascular Genetics 12/2014; · 5.34 Impact Factor
Peter J P Croucher