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Background Lymphedema (LE) is a chronic clinical manifestation of filarial nematode infections characterized by lymphatic dysfunction and subsequent accumulation of protein-rich fluid in the interstitial space—lymphatic filariasis. A number of studies have identified single nucleotide polymorphisms (SNPs) associated with primary and secondary LE. To assess SNPs associated with LE caused by lymphatic filariasis, a cross-sectional study of unrelated Ghanaian volunteers was designed to genotype SNPs in 285 LE patients as cases and 682 infected patients without pathology as controls. One hundred thirty-one SNPs in 64 genes were genotyped. The genes were selected based on their roles in inflammatory processes, angiogenesis/lymphangiogenesis, and cell differentiation during tumorigenesis. Results Genetic associations with nominal significance were identified for five SNPs in three genes: vascular endothelial growth factor receptor-3 (VEGFR-3) rs75614493, two SNPs in matrix metalloprotease-2 (MMP-2) rs1030868 and rs2241145, and two SNPs in carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) rs8110904 and rs8111171. Pathway analysis revealed an interplay of genes in the angiogenic/lymphangiogenic pathways. Plasma levels of both MMP-2 and CEACAM-1 were significantly higher in LE cases compared to controls. Functional characterization of the associated SNPs identified genotype GG of CEACAM-1 as the variant influencing the expression of plasma concentration, a novel finding observed in this study. Conclusion The SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development. Electronic supplementary material The online version of this article (10.1186/s40246-017-0121-7) contains supplementary material, which is available to authorized users.

Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

Item does not contain fulltext 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 fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 x 10(-8)

Summary Background 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 which no candidate gene has yet been identified. Objectives To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. Methods Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. Results Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. Conclusions The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.

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 selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.

Summary Background Male-pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X-chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. Objectives To identify further candidate genes for AGA, and thus gain further insights into this phenotype. Methods A German sample of 581 severely affected cases and 617 controls was used to perform a genome-wide association study. The identified associated locus was further analysed by fine-mapping, and then independently replicated in an Australian sample. Expression and pathway analyses were performed to characterize the susceptibility gene identified. Results The most significant association signal was obtained for rs756853 (P = 1·64 × 10−7), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6-kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian sample, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined sample of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10−8). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype-specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. Conclusions The present study suggests that HDAC9 is the third AGA susceptibility gene.

Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 x 10(-4) (OR=1.24 (1.10-1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA. European Journal of Human Genetics (2012) 20, 326-332; doi:10.1038/ejhg.2011.185; published online 26 October 2011

De Novo Duplication of 18p11.21–18q12.1 in a Female With Anorectal Malformation Charlotte Schramm, Markus Draaken, Enrika Bartels, Thomas M. Boemers, Eberhard Schmiedeke, Sabine Grasshoff-Derr, Stefanie M€arzheuser, Stuart Hosie, Stefan Holland-Cunz, Friederike Baudisch, Lutz Priebe, Per Hoffmann, Alexander M. Zink, Hartmut Engels, Felix F. Brockschmidt, Stefan Aretz, Markus M. N€othen, Michael Ludwig, and Heiko Reutter* Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany Department of Pediatric Surgery and Pediatric Urology, Children’s Hospital, Cologne, Germany Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany Department of Pediatric Surgery, University Hospital W€urzburg, W€urzburg, Germany Department of Pediatric Surgery, Campus Virchow Clinic, Charit e University Hospital Berlin, Berlin, Germany Department of Pediatric Surgery, Klinikum Schwabing, Technische Universit€at M€unchen, M€unchen, Germany Department of Pediatric Surgery, University of Heidelberg, Heidelberg, Germany Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany Department of Neonatology, Children’s Hospital, University of Bonn, Bonn, Germany

Summary Background Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). Objectives To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1195 patients with AA and 1280 controls. Methods We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. Results While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0·004, Pcorr = 0·026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. Conclusions Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

Zusammenfassung Die androgenetische Alopezie (AGA, erblich- bzw. hormonbedingter Haarausfall [MIM 109200; MIM 300710; MIM 612421]) ist die häufigste Form des Haarverlusts beim Menschen, wobei die Prävalenz stark altersabhängig ist. Im Alter von über 70 Jahren sind über 80% der europäischen Männer betroffen, bei Frauen liegt die AGA-Häufigkeit mit 30–40% deutlich niedriger. Die AGA führt, v. a. bei betroffenen Frauen, zu einer erheblichen psychologischen Belastung und entfaltet dabei Krankheitswert. Der Haarverlust geht auf einen veränderten Haarzyklus und eine Miniaturisierung des Haarfollikels zurück. Die Pathogenese ist androgenabhängig, und die genetische Anlage ist wesentliche Voraussetzung für den Phänotyp. In mehreren Studien konnten der Androgenrezeptor-/Ektodysplasin-A2-Rezeptor(EDA2R)-Locus auf dem X-Chromosom als stärkster beitragender Faktor und durch genomweite Assoziationsuntersuchungen ein weiterer Locus auf Chromosom 20p11 identifiziert werden. Das zum Assoziationssignal nächstgelegene in der Kopfhaut exprimierte Gen ist „paired box 1“ (PAX1). Zwischen PAX1 und dem Androgensignalweg gibt es keine offensichtliche Verbindung, jedoch sind die dem Assoziationssignal auf Chromosom 20p11 zugrunde liegenden pathophysiologischen Prozesse noch nicht geklärt. Bis heute ermöglichen die zur Verfügung stehenden medikamentösen Therapien der AGA bestenfalls ein Aufhalten des Haarverlusts. Mit der Identifizierung der AGA-assoziierten Gene und der Aufklärung ihrer Funktionen wird man die biologischen Ursachen der AGA schrittweise erschließen. Damit ist die Hoffnung auf die Entwicklung neuer Therapien verbunden.

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome.

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

Item does not contain fulltext Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 x 10(-5); follow-up: P = 0.0025; combined: 1.09 x 10(-6)) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.

We carried out a genome-wide association study in 296 individuals with male-pattern baldness (androgenetic alopecia) and 347 controls. We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)). No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.

Summary Background Male pattern baldness (androgenetic alopecia, AGA) is a highly heritable trait and the most common form of hair loss in humans. Eight genome-wide significant risk loci for AGA have been identified. Objectives To determine whether a polygenic component contributes to the genetic risk for AGA. Methods This study used a German case–control sample for AGA, which comprised 581 severely affected patients and 617 controls, to determine the contribution of polygenic variance to AGA risk. The sample was divided evenly into discovery and test samples. An additive polygenic risk score was calculated from risk alleles with increasingly liberal P-values in the discovery dataset, which was then used to test for the enrichment of AGA risk score alleles in the independent test samples. Results The polygenic score analysis provided significant evidence for a polygenic contribution to AGA where the amount of variance explained was 1·4–4·5%. Conclusion This study provides evidence for the specific contribution of a polygenic component to the overall heritable risk for AGA. To some degree, the polygenic architecture of AGA might reflect the complexity of the biological pathways involved. Further analyses and strategies that complement conventional genome-wide association studies are needed to identify these factors. These may include pathway-based analyses, the analysis of functional candidate genes and tests for epistatic effects with known loci.

In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration.

Summary Background Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. Objectives To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. Methods Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. Results Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10−6). Conclusions Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

International audience; Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42*), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542þ1_542þ4delGTAA, r.421_542del, p.Glu181Glyfs*20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolution-arily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex. With a worldwide prevalence of around 2%, early-onset cognitive impairment, commonly referred to as intellectual disability (ID), is the most frequent cause of severe disability and a leading socioeconomic healthcare problem in Western countries. 1 For the last two decades, remarkable progress has been made in the elucidation of ID conditions. About 30% percent of severe ID cases have been ascribed to chromosomal imbalances. 2 Defects in X-linked genes account for about 10% of male ID cases. 3 Yet despite these recent advances, the cause of ID remains unexplained in the majority of cases, and this leaves families without accurate diagnosis or genetic counseling. In particular , very little is known about the autosomal-recessive forms of ID (ARID). The broad genetic heterogeneity of ARID precludes any possibility of pooling families, and the scarcity of large pedigrees suitable for linkage analyses have hitherto hampered identification of the genes responsible for most of these cases. This problem has been successfully circumvented by the use of autozygosity mapping in large consanguineous families; in nonspecific ARID ten genes have been identified so far. 1,4-12 Nevertheless , mutations in each of these genes only account for one or very few families, suggesting that many genes remain to be identified. Here, we present linkage analyses, mutation discovery, and clinical characterization of a recognizable ARID syndrome in eight affected individuals from three consan-guineous families. Family ID01 is a sibship of three affected and two healthy siblings born to healthy parents, who are second cousins of Israeli-Arab descent (Figure 1A and Table 1). Pregnancy and delivery were unremarkable in all three affected cases. At birth all three siblings presented with microcephaly and muscular hypotonia, which later developed to hypertonia. At the time of examination, a clinical assessment showed hyperreflexia, spastic paraplegia, and an inability to walk unaided. All affected individuals revealed a severe cognitive deficit, marked speech delay, and adaptive impairment. Furthermore, they presented with microcephaly, a high palate, mildly remarkable facial gestalt with a wide nasal bridge, short stature, hyperlaxity, genu recurvatum, pes planus, and a waddling gait. All three affected individuals had stereotypic laughter and markedly shy character. None of the patients had seizures, vision or

The non-random association of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with esophageal atresia (TE), renal malformations (R), and limb defects (L) is termed VACTERL association. The aim of the present study was to identify microaberrations characterized by a loss or gain of genomic material that contribute to VACTERL association at a genome-wide level. Molecular karyotyping was performed in a cohort of 12 patients with anorectal malformations and at least two additional cardinal features of the VACTERL association. A de novo microduplication at chromosomal region 22q11.21 was identified in a patient presenting with three cardinal VACTERL features (V, A, R) and vesicoureteral reflux, penile hypospadias, caudal regression syndrome, and right-sided congenital equinovarus deformity. Chromosomal region 22q11.2 is known for its susceptibility to rearrangements. Associated syndromes include the velo-cardio-facial and DiGeorge deletion syndromes, and the complementary 22q11.2 duplication syndrome. The findings of the present study extend the phenotypic spectrum of the 22q11.2 duplication syndrome, and indicate that it also predisposes to VACTERL association. We discuss the overlap between the phenotypic features of our patient and those reported for other 22q11.2 aberrations, and propose that dosage-sensitive loci for all of these phenotypic features may reside on 22q11.2.

Strong evidence of linkage between chromosomal region 6q16-q22 and bipolar affective disorder (BPAD) has previously been reported. We conducted a systematic association mapping of the 6q-linkage interval using 617 SNP markers in a BPAD case–control sample of German descent (cases = 330, controls = 325). In this screening step, 46 SNPs showed nominally significant BPAD-association (P-values between 0.0007 and 0.0484). Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample (cases = 328, controls = 397). At the melanin-concentrating-hormone-receptor-2 (MCHR2) gene, we found nominal association in both the initial and second BPAD samples (combined P = 0.008). This finding was followed up by the genotyping of 17 additional MCHR2-SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2-locus can be divided into three different haplotype-blocks, and observed that the MCHR2-association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative risk-haplotypes were found to be 7% more frequent in patients (block II: 23.3% vs. 16.2%, P = 0.005, block III: 39.2% vs. 32.0%, P = 0.024), whereas the putative protective haplotypes were found to be 5–8% less frequent in patients (block II: 11.6% vs. 16.4%, P = 0.041, block III: 30.0% vs. 38.8%, P = 0.007). The corresponding odds ratios (single-marker analysis) ranged between 1.25 and 1.46. Our findings may indicate that MCHR2 is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples.

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.

Genetic variants in the human androgen receptor gene (AR) are associated with male pattern baldness (androgenetic alopecia, AGA) in Europeans. Previous observations of long-range linkage disequilibrium at the AR locus are consistent with the hypothesis of recent positive selection. Here, we further investigate this signature and its relationship to the AGA risk haplotype. The haplotype homozygosity suggests that the AGA risk haplotype was driven to high frequency by positive selection in Europeans although a low meiotic recombination rate contributed to the high haplotype homozygosity. Further, we find high levels of population differentiation as measured by F ST and a series of fixed derived alleles along an extended region centromeric to AR in the Asian HapMap sample. The predominant AGA risk haplotype also carries the putatively functional variant 57K in the flanking ectodysplasin A2 receptor gene (EDA2R). It is therefore probable that the AGA risk haplotype rose to high frequency in combination with this EDA2R variant, possibly by hitchhiking on a positively selected 57K haplotype. Electronic supplementary material The online version of this article (doi:10.1007/s00439-009-0668-z) contains supplementary material, which is available to authorized users.

Background: With the beginning of the era of genome-wide association studies methods to obtain ‘in silico’ genotypes have gained importance. In this context, an evaluation of genome-wide power levels of current marker panels and the power gain achievable with imputed genotypes are of high interest. Methods: Power for single-marker analysis of imputed genotypes is evaluated via a simulation study based on HapMap data. Power values for genome-wide significance of marker panels of 1,000,000 SNPs are considered for small effect sizes typical of common diseases and large case-control samples. In order to evaluate the performance of imputing, we consider a method that is conceptually related to previous approaches. We introduce various modifications which together lead to an alternative implementation of the imputation idea. In particular, a Monte-Carlo (MC) simulation method for association testing of imputed markers is introduced. Results: We show that the incorporation of imputed genotypes can lead to a substantial power gain for common disease variants if the training sample is large enough. In addition, we show that the MC approach is valuable to for validating association results obtained with imputed genotypes. Discussion: Our simulation study also shows that even denser marker panels than those currently available are needed when sample size is limited. We thus expect that full genome SNP panels will lead to the identification of additional disease variants in the future. Until then, it is desirable that large and ethnically matched training samples genotyped on dense marker panels are available in each country.

Genetic studies have reported association of a polyglycine-encoding GGN repeat in exon 1 of the androgen receptor (AR) gene with common human traits. The polyglycine tract is located in the transactivating domain of the AR protein, suggesting an effect of repeat length on receptor function. Here, we compare the functional characteristics of the two most common alleles (23 and 24 repeats) and two extreme alleles (10 and 27 repeats) in a reporter gene assay in HeLa cells. A correlation between the repeat length and AR activity was observed. This is attributable to both a higher protein concentration, determined by ELISA, and a higher per-protein activity of long repeat alleles. Interestingly, protein concentration does not correlate with transcript quantity, determined by real-time PCR assays, and no influence of repeat length on protein stability could be detected in translation inhibition assays. This may suggest that repeat length affects translation efficiency. In conclusion, our data provide evidence of functional differences between the two most common alleles of the AR GGN repeat, supporting its potential role in the development of human traits.

A family-based and case–control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder

Androgenetic alopecia (AGA, male pattern baldness) is the most common form of hair loss. The origin of AGA is genetic, with the X chromosome located androgen receptor gene (AR) being the only risk gene identified to date. We present the results of a genome-wide linkage study of 95 families and linkage fine mapping of the 3q21-q29, 11q14-q25, 18p11-q23, and 19p13-q13 regions in an extended sample of 125 families of German descent. The locus with strongest evidence for linkage was mapped to 3q26 with a nonparametric linkage (NPL) score of 3.97 (empirical p value = 0.00055). This is the first step toward the identification of new susceptibility genes in AGA, a process which will provide important insights into the molecular and cellular basis of scalp hair loss.

Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value