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Objective The objective was to develop a dataset definition, information model, and FHIR® specification for key data elements contained in a German molecular genomics (MolGen) report to facilitate genomic and phenotype integration in electronic health records. Materials and Methods A dedicated expert group participating in the German Medical Informatics Initiative reviewed information contained in MolGen reports, determined the key elements, and formulated a dataset definition. HL7’s Genomics Reporting Implementation Guide (IG) was adopted as a basis for the FHIR® specification which was subjected to a public ballot. In addition, elements in the MolGen dataset were mapped to the fields defined in ISO/TS 20428:2017 standard to evaluate compliance. Results A core dataset of 76 data elements, clustered into 6 categories was created to represent all key information of German MolGen reports. Based on this, a FHIR specification with 16 profiles, 14 derived from HL7®’s Genomics Reporting IG and 2 additional profiles (of the FamilyMemberHistory and RiskAssessment resources), was developed. Five example resource bundles show how our adaptation of an international standard can be used to model MolGen report data that was requested following oncological or rare disease indications. Furthermore, the map of the MolGen report data elements to the fields defined by the ISO/TC 20428:2017 standard, confirmed the presence of the majority of required fields. Conclusions Our report serves as a template for other research initiatives attempting to create a standard format for unstructured genomic report data. Use of standard formats facilitates integration of genomic data into electronic health records for clinical decision support.

IntroductionFormal genetics studies show that smoking is influenced by genetic factors; exploring this on the molecular level can offer deeper insight into the etiology of smoking behaviours.MethodsSummary statistics from the GWAS and Sequencing Consortium of Alcohol and Nicotine (GSCAN) Consortium were used to calculate polygenic risk scores (PRS) in a sample of ∼2,200 smokers/never-smokers. The association of PRS for Smoking Initiation (i.e. Lifetime Smoking; SI-PRS) with smoking status, and PRS for Cigarettes per Day (CpD-PRS) and Smoking Cessation (SC-PRS) with Fagerström Test for Nicotine Dependence (FTND) score were examined, as were distinct/additive effects of parental smoking on smoking status.ResultsSI-PRS explained 6.65% of variance (Nagelkerke-R2) in smoking status (p=1.71×10−24). In smokers, CpD-PRS (R2=3.15%, p=1.82×10−8) and SC-PRS (R2=2.01%; p=7.18×10−6) were associated with FTND score. Parental smoking alone explained R2=3.06% (p=2.43×10−12) of smoking status, and 1.39% when added to the most informative SI-PRS model (total R²=8.04%).ConclusionThese results show the potential utility of molecular genetic data for research investigating smoking prevention. The fact that PRS explains more variance than family history highlights progress from formal to molecular genetics; the overlap and increased predictive value when using both suggests the importance of combining these approaches.ImplicationsThis study underlines the value of using PRS to predict smoking status/behaviour. It highlights the importance of molecular genetic methods in research investigating smoking prevention and points to the necessity of combining family history and molecular genetic data.

Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development.Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations. The current study paved the way for identification of responsible genes in two unrelated Iranian families.We found two novel nonsense mutations, p.C77* and p.Q115*, in the calpain catalytic domain of CAPN10, which is a cysteine protease known to be involved in pathogenesis of noninsulin-dependent diabetes mellitus. Another different mutation in this gene (p.S138_R139ins5) has previously been reported in an Iranian family. All of these patients have common clinical features in spite of specific brain structural abnormalities on MRI.Different mutations in CAPN10 have already been found in three independent Iranian families. These results have strongly supported the possible role of CAPN10 in human brain development. Altogether, we proposed CAPN10 as a promising candidate gene for intellectual disability, which should be considered in diagnostic gene panels.

Cigarette smoking is a severe health burden being related to a number of chronic diseases. Frequently, smokers report about sleep problems. Sleep disturbance, in turn, has been demonstrated to be involved in the pathophysiology of several disorders related to smoking and may be relevant for the pathophysiology of nicotine dependence. Therefore, determining the frequency of sleep disturbance in otherwise healthy smokers and its association with degree of nicotine dependence is highly relevant. In a population-based case-control study, 1071 smokers and 1243 non-smokers without lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorder were investigated. Sleep quality (SQ) of participants was determined by the Pittsburgh Sleep Quality Index. As possible confounders, age, sex and level of education and income, as well as depressiveness, anxiety, attention deficit hyperactivity, alcohol drinking behaviour and perceived stress, were included into multiple regression analyses. Significantly more smokers than non-smokers (28.1% versus 19.1%; P 0.0001) demonstrated a disturbed global SQ. After controlling for the confounders, impaired scores in the component scores of sleep latency, sleep duration and global SQ were found significantly more often in smokers than non-smokers. Consistently, higher degrees of nicotine dependence and intensity of smoking were associated with shorter sleep duration. This study demonstrates for the first time an elevated prevalence of sleep disturbance in smokers compared with non-smokers in a population without lifetime history of psychiatric disorders even after controlling for potentially relevant risk factors. It appears likely that smoking is a behaviourally modifiable risk factor for the occurrence of impaired SQ and short sleep duration.

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine-Molecular and Physiological Effects in CNS', was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.

P50 gating is a major functional biomarker in research on schizophrenia and other psychiatric conditions with high smoking prevalence. It is used as endophenotype for studying nicotinic systems genetics and as surrogate endpoint measure for drug development of nicotinic agonists. Surprisingly, little is known about P50 gating in the general population and the relationship to smoking-related characteristics. In this multicenter study at six academic institutions throughout Germany, n=907 never-smokers (NS20 cigarettes/lifetime), n=463 light smokers (LS) with Fagerström Test for Nicotine Dependence (FTND)≥4 and n=353 heavy smokers (HS, FTND4) were randomly selected from the general population. As part of a standardized protocol for investigating the genetics of nicotine dependence (ND), an auditory P50 paradigm was applied. The main outcome measure was P50-amplitude difference followed by time-frequency analyses and functional imaging (sLORETA). Reduced P50 gating was found in HS compared to NS with LS taking an intermediate position-correlating with the degree of ND. sLORETA and time-frequency analyses indicate that high-frequency oscillations in frontal brain regions are particularly affected. With growing age, P50 gating increased in (heavy) smokers. This is the first large-scale study (normative sample data) on P50 sensory gating and smoking in the general population. Diminished gating of P50 and associated high-frequency oscillations in the frontal brain region are indications of a deficient inhibitory cortical function in nicotine-dependent smokers. The suitability and application of sensory P50 gating as functional biomarker with regard to genetic and pharmacological studies is discussed.

Background. There is increasing evidence suggesting that genes located on the short arm of chromosome 11 play an important role in the development of human ovarian cancer. Recent cytogenetic and molecular studies have demonstrated the loss of genetic material in this region. Loss of normal growth regulatory genes may allow for the expression of tumorigenicity or lead to tumor progression. Methods. The authors used DNA recombinant techniques to examine the frequency of allelic losses at four loci spanning the chromosomal region 11p15.1–11p15.5 in 40 patients with malignant ovarian tumors. DNA extracts from normal leukocytes and 48 tumor samples were analyzed by Southern blotting using the polymorphic probes pEJ6.6 (HRAS1), phins310 (INS), p20.36 (PTH), and pEM36 (CALCA). Results. Reduction to homozygosity in the tumor DNA was found in 47.5% of the informative cases (19 of 40). Comparing the results with clinical parameters, none of the well-differentiated tumors (6 of 40, Grade 1) and only one of the early stage tumors (6 of 40, International Federation of Gynecology and Obstetrics [FIGO] Stage I or II) showed alterations in this chromosome region. Statistical analysis revealed a strong correlation of rate of loss of constitutional heterozygosity (LOH) and grade of differentiation, in the sense of higher 11p allele losses occurring in poorly differentiated tumors. Conclusions. The authors concluded that the relatively high incidence of 11p allele losses marks an important step in ovarian cancer development. Furthermore, statistical analysis showed that loss of 11p alleles was strongly correlated with poorly differentiated ovarian cancer, indicating the location of genes involved in cellular functions associated with the development of more anaplastic tumors.