Nonmalignant Formalin-Fixed Paraffin-Embedded Tissues as a Source to Study Germline Variants and Cancer Predisposition : A Systematic Review

Background:Archived formalin-fixed paraffin-embedded (FFPE) specimens from nonmalignant tissues derived from cancer patients are a vast and potentially valuable resource for high-quality genotyping analyses and could have a role in establishing inherited cancer risk. Methods:We systematically searched PubMed, Ovid MEDLINE, and Scopus databases for all articles that compared genotyping performance of DNA from nonmalignant FFPE tissue with blood DNA derived from cancer patients irrespective of tumor type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies, and extracted genotyping data from the eligible studies. These studies included, but were not limited to, genotyping technique, reported call rate, and concordance. Results:Thirteen studies were reviewed, in which DNA from nonmalignant FFPE tissues derived from cancer patients was successfully purified and genotyped. All these studies used different approaches for genotyping of DNA from nonmalignant FFPE tissues to amplify single nucleotide polymorphisms (SNPs) and to estimate of loss of heterozygosity. The concordance between genotypes from nonmalignant FFPE tissues and blood derived from cancer patients was observed to be high, whereas the call rate of the tested SNPs was not reported in all included studies. Conclusion:This review illustrates that DNA from nonmalignant FFPE tissues derived from cancer patients can serve as an alternative and reliable source for assessment of germline DNA for various purposes, including assessment of cancer predisposition.Peer reviewe

Is Brain-Derived Neurotrophic Factor Associated With Smoking Initiation? Replication Using a Large Finnish Population Sample : Replication Using a Large Finnish Population Sample

Introduction: Brain-derived neurotrophic factor (BDNF) is a growth factor in the central nervous system. There is evidence for the involvement of BDNF in addictions and mental disorders. We aimed to replicate the earlier reported association of a functional genetic variant of BDNF with smoking initiation (SI) using a large population-based sample and to test whether the association is independent of depression. Methods: Our sample was drawn from the Finnish population-based FINRISK surveys conducted in 1992, 1997, 2002, and 2007. We had nonmissing data on the genotype BDNF Val66Met (G/A) variant (rs6265) and self-reported never (n = 10 619) versus ever (n = 16 028) smoking among 26 647 adults aged 25-74 years. The association between BDNF Val66Met and SI was modeled using logistic regression adjusted for age and sex, and in secondary analyses also for depression. Depression was defined as self-reported depression diagnosed or treated by physician during the past year. Results:The sex- and age-adjusted analysis confirmed that the major (Val) allele increased the risk of being a lifetime ever smoker (per allele odds ratio [OR] = 1.07; 95% CI = 1.01 to 1.12; p =.01). When depression, which itself was significantly associated with SI (OR = 1.58; 95% CI = 1.37 to 1.82; p Conclusions: In a Finnish population sample, we replicated the earlier reported association of BDNF Val66Met with SI. Our data further suggest that this association is independent of depression.Peer reviewe

Tautimekanismien jäljille iPS-solujen ja biopankkien avulla

Vertaisarvioitu.Indusoidut pluripotentit kantasolut, eli iPS-solut, ovat tavallisista somaattisista soluista tuotettuja kantasoluja, joilla on kyky erilaistua kaikiksi yksilönkehityksen aikana kehittyviksi solutyypeiksi. iPS-solut ovat lyhyessä ajassa mullistaneet useiden sairauksien tutkimusmahdollisuudet, ja niitä käytetään lisääntyvästi sekä tautimallinnuksessa että uusien lääkkeiden ja hoitomuotojen kehittämisessä. Suurimmat läpimurrot on saavutettu monogeenisten sairauksien tutkimuksessa, jossa potilaista tuotetuilla soluilla on keskeinen rooli, mutta edistysaskeleita on otettu myös monitekijäisten sairauksien ymmärtämisessä. Näytemäärien kasvaessa biopankkien merkitys iPS-solulinjojen ja niistä kerätyn tiedon systemoidussa tallentamisessa ja hallinnoinnissa on korostunut. Yhdessä genomitiedon kanssa biopankkitoiminta tarjoaa Suomessa erinomaiset edellytykset hyödyntää iPS-soluja biolääketieteellisessä tutkimuksessa.Peer reviewe

Data-driven comorbidity analysis of 100 common disorders reveals patient subgroups with differing mortality risks and laboratory correlates

The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials.Peer reviewe

Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci

Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.Peer reviewe

Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 x 10(-9)), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappa B transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 x 10(-9)), and on 11p15 (P = 6.6 x 10(-8)) in an intron of AP2A2, and P = 4.2 x 10(-7) for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 x 10(-8)) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.Peer reviewe

Model-based assessment of replicability for genome-wide association meta-analysis

Genome-wide association meta-analysis (GWAMA) is an effective approach to enlarge sample sizes and empower the discovery of novel associations between genotype and phenotype. Independent replication has been used as a gold-standard for validating genetic associations. However, as current GWAMA often seeks to aggregate all available datasets, it becomes impossible to find a large enough independent dataset to replicate new discoveries. Here we introduce a method, MAMBA (Meta-Analysis Model-based Assessment of replicability), for assessing the “posterior-probability-of-replicability” for identified associations by leveraging the strength and consistency of association signals between contributing studies. We demonstrate using simulations that MAMBA is more powerful and robust than existing methods, and produces more accurate genetic effects estimates. We apply MAMBA to a large-scale meta-analysis of addiction phenotypes with 1.2 million individuals. In addition to accurately identifying replicable common variant associations, MAMBA also pinpoints novel replicable rare variant associations from imputation-based GWAMA and hence greatly expands the set of analyzable variants.Peer reviewe

The effect of body mass index on smoking behaviour and nicotine metabolism : a Mendelian randomization study

Given clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight. We performed Mendelian randomization (MR) analyses of the effects of BMI on smoking behaviour in UK Biobank and the Tobacco and Genetics Consortium genome-wide association study (GWAS), on cotinine levels and nicotine metabolite ratio (NMR) in published GWAS and on DNA methylation in the Avon Longitudinal Study of Parents and Children. Our results indicate that higher BMI causally influences lifetime smoking, smoking initiation, smoking heaviness and also DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus, but we do not see evidence for an effect on smoking cessation. While there is no strong evidence that BMI causally influences cotinine levels, suggestive evidence for a negative causal influence on NMR may explain this. There is a causal effect of BMI on smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism.Peer reviewe