Dmitriy Drichel

University of Cologne | UOC

Background: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. Methods: To id...

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide s...

Region-based genome-wide scans are usually performed by use of a priori chosen analysis regions. Such an approach will likely miss the region comprising the strongest signal and, thus, may result in increased type II error rates and decreased power. Here, we propose a genomic exhaustive scan approach that analyzes all possible subsequences and does...

Region-based genome-wide scans are usually performed by use of a priori chosen analysis regions. Such an approach will likely miss the region comprising the strongest signal and, thus, may result in increased type II error rates and decreased power. Here, we propose a genomic exhaustive scan approach that analyzes all possible subsequences and does...

OBJECTIVE: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Haz...

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the indiv...

The original version of this Article contained an error in the spelling of the author Robert Häsler, which was incorrectly given as Robert Häesler. This has now been corrected in both the PDF and HTML versions of the Article.

FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantl...

Background Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular sig...

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene gr...

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10−8, METAL)...

Supplementary Figures, Supplementary Tables, Supplementary Note, and Supplementary References

Results of the enhancer enrichment analysis of MPB credible SNPs at the 63 genome-wide significant risk loci.

Shared genetic determinants between MPB and other human traits. MPB SNP - MPB lead SNP; GWAS SNP - reported GWAS SNP; CHR - chromosome, BP - base pair; EA - effect allele; OR - odds ratio; BETA - effect size; CI - confidence interval; MPB EA GWAS SNP - effect allele of GWAS SNP in MPB meta-analysis; LD - linkage desequilibrium; NR- not reported; +...

Functional description of genes that were identified as plausible candidate genes based on at least two of the following criteria: expression in human hair follicle (E), functional evidence from literature (F), vicinity to MPB lead SNP (N), evidence for cis-eQTL effect (Q), evidence from DEPICT analysis (D) (see Table 1). Chr. – Chromosome; PMID –...

Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in a...

In up to 30 % of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative...

A usually confronted problem in association studies is the occurrence of population stratification. In this work, we propose a novel framework to consider population matchings in the contexts of genome-wide and sequencing association studies. We employ pairwise and groupwise optimal case-control matchings and present an agglomerative hierarchical c...

Background: In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aime...

Important methodological advancements in rare variant association testing have been made recently, among them collapsing tests, kernel methods and the variable threshold (VT) technique. Typically, rare variants from a region of interest are tested for association as a group ('bin'). Rare variant studies are already routinely performed as whole-exom...

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of...

Motivation: Meta-analysis of summary statistics is an essential approach to guarantee the success of genome-wide association studies (GWAS). Application of the fixed or random effects model to single-marker association tests is a standard practice. More complex methods of meta-analysis involving multiple parameters have not been used frequently, a...

Cerebrospinal fluid amyloid-beta 1–42 (Aβ1–42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1–42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1–42 level...

We present a genome-wide association study of a quantitative trait, "progression of systolic blood pressure in time," in which 142 unrelated individuals of the Genetic Analysis Workshop 18 real genotype data were analyzed. Information on systolic blood pressure and other phenotypic covariates was missing at certain time points for a considerable pa...

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA loc...

The aetiopathogenesis of female pattern hair loss (FPHL) is poorly understood. Although research has strongly implicated genetic factors in familial occurrence, no association finding for FPHL has yet been replicated. Consequently, no causal biological pathways can be suggested on the basis of currently available genetic findings. A recent gene-wid...

Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are overly simplistic. In this context, it was recent...

MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are, so far, hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina...

Modeling of the miRNA down- and upregulation in metastasis tissues of patient 3,4,5 and 7. (PPT)

List of 25 most significantly differentially expressed miRNAs N/T, N/M, T/M. (XLS)

Ligands and receptors as well as downstream signaling pathways integrated in the computer model. (XLS)

Targets of miRNA-1. (XLS)

Changes in miRNA expression between normal, tumor and metastasis tissues. (PPT)

Complete clinical information of the colorectal cancer patients. (XLS)

Complete lists of miRNAs detected in (A) N/T, (B) N/M and (C) T/M. (XLS)

Output of the modeling system. (XLS)

Significantly de-regulated miRNAs (p-value <0.05) which are also listed in the PhenomiR database. (XLS)

Marker combinations for the discrimination of normal/tumor, normal/metastasis, normal/tumor and metastasis and tumor/metastasis tissues. (PPT)

Clinical information of samples for the screen of different tumor entities. (XLS)

Small RNA sequencing statistic. (XLS)

mRNA sequencing statistic for colon cancer patients. (XLS)

The initial conditions of miRNA-1 down-regulation of an individual sample. (XLS)

The initial conditions of miRNA-1 up-regulation of an individual. (XLS)

Validation of the Illumina sequencing data. (DOCX)

Supplementary methods. (DOCX)

SBML file of the Signaling Cancer Model. (XML)

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA-development. However a significant f...

Female pattern hair loss (FPHL) is a common hair loss disorder in women with a complex mode of inheritance. Its etiopathogenesis is poorly understood. Widespread assumptions of overlapping susceptibility variants between FPHL and male pattern baldness (androgenetic alopecia) and a crucial role of androgens or distinct sexual steroid hormones in the...

Meta-analysis (MA) is widely used to pool genome-wide association studies (GWASes) in order to a) increase the power to detect strong or weak genotype effects or b) as a result verification method. As a consequence of differing SNP panels among genotyping chips, imputation is the method of choice within GWAS consortia to avoid losing too many SNPs...

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore s...

Pathway association analysis (PAA) tests for an excess of moderately significant SNPs in genes from a common pathway. We present a Monte-Carlo simulation framework that allows to formulate the main ideas of existing PAA approaches using a self-contained rather than a competitive null hypothesis. A stand-alone implementation in INTERSNP makes time-c...

The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for whi...