A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype

Background Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. Methods Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. Results We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. Conclusions Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features—particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry—should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

J. Kaprio, A. Palotie, A. Raevuori-Helkamaa ja S. Ripatti ovat työryhmän Eating Disorders Working Group of the Psychiatric Genomics Consortium jäseniä. Erratum in: Sci Rep. 2017 Aug 21;7(1):8379, doi: 10.1038/s41598-017-06409-3We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.Peer reviewe

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

An incomplete European barcode library has a strong impact on the identification success of Lepidoptera from Greece

Abstract Species identification by means of DNA barcodes depends essentially on the scope and quality of a relevant reference library. The first analysis of a large number (about 600 morphospecies) of southern European Lepidoptera (Greece: Peloponnese) shows both the advantages and disadvantages with regard to a reliable identification of Mediterranean species. We determined 946 DNA barcode sequences from 47 families, of which 929 sequences from 46 families were successfully assigned to a Barcode Index Number (BIN) in the global Barcode of Life Data Systems (BOLD) database. A species level identification for 485 BINs representing 477 Linnaean names was successful. These taxa include 34 new records for Greece. However, 128 BINs (c. 20% of the inventory) could not be attached to a Linnaean name from referenced sequences available in BOLD. Of these BINs, 99 are new and hence represent unique records for BOLD. Intra- and inter-BIN divergences are presented and discussed. An initial and preliminary in-depth analysis of randomly selected species indicates an incomplete DNA barcode library in terms of Linnean taxa, in addition to a considerable number of probably undescribed species. It is therefore strongly recommended that the already advanced European barcode library of Lepidoptera should be supplemented with not-yet-sequenced taxa from the Mediterranean

Pruning the barcode index numbers tree:morphological and genetic evidence clarifies species boundaries in the Eupithecia conterminata complex (Lepidoptera: Geometridae) in Europe

Abstract The Barcode Index Numbers (BINs) are operational species units based on patterns of COI divergences that in most cases correspond to species. It has been repeatedly observed that more than one BIN can be found under the same species name particularly when large geographic scales are considered. One such case concerns Eupithecia conterminata, a species widespread in North European countries and restricted to mountainous regions in the rest of the continent, for which five BINs are found in Europe. In order to solve the question concerning the taxonomic status of these BINs and European populations, we employed an integrated approach by combining classical morphological traits (genitalia and wing markings) with those of molecular data, the latter involving both mitochondrial and nuclear genes. This approach allowed us to recognize two valid species in Europe, E. conterminata, currently known only in Fennoscandia, Baltic countries and Russia, and Eupithecia manniaria sp. rev., with distribution covering Central and South European countries. We furthermore synonymized Eupithecia pindosata syn. nov. from Greece with E. manniaria. The European range of these species and their mitochondrial diversity appear to be coherent with biogeographical histories of their foodplants Picea abies and Abies species

DNA barcoding and genomics reveal Perizoma barrassoi Zahm, Cieslak & Hausmann, 2006 as new for the fauna of Central Europe (Lepidoptera, Geometridae, Larentiinae)

Abstract Perizoma barrassoi Zahm, Cieslak & Hausmann, 2006, previously considered a central Italian endemic, shows a much wider distribution with additional records from the Alps and the Pyrenees, in partial sympatry with its sister species, Perizoma incultaria (Herrich-Schäffer, 1848) which is widespread in the Alps, Pyrenees, Carpathians and Dinaric mountains. The disruptive genetic patterns of both species involve the COI barcode gene as well as nuclear genomic data and are confirmed by correlated differential features in male and female genitalia. To fix nomenclatural stability a neotype is designated for P. incultaria