Clustering long-term health conditions among 67728 people with multimorbidity using electronic health records in Scotland.

There is still limited understanding of how chronic conditions co-occur in patients with multimorbidity and what are the consequences for patients and the health care system. Most reported clusters of conditions have not considered the demographic characteristics of these patients during the clustering process. The study used data for all registered patients that were resident in Fife or Tayside, Scotland and aged 25 years or more on 1st January 2000 and who were followed up until 31st December 2018. We used linked demographic information, and secondary care electronic health records from 1st January 2000. Individuals with at least two of the 31 Elixhauser Comorbidity Index conditions were identified as having multimorbidity. Market basket analysis was used to cluster the conditions for the whole population and then repeatedly stratified by age, sex and deprivation. 318,235 individuals were included in the analysis, with 67,728 (21·3%) having multimorbidity. We identified five distinct clusters of conditions in the population with multimorbidity: alcohol misuse, cancer, obesity, renal failure, and heart failure. Clusters of long-term conditions differed by age, sex and socioeconomic deprivation, with some clusters not present for specific strata and others including additional conditions. These findings highlight the importance of considering demographic factors during both clustering analysis and intervention planning for individuals with multiple long-term conditions. By taking these factors into account, the healthcare system may be better equipped to develop tailored interventions that address the needs of complex patients.

Beacon v2 and Beacon networks: A "lingua franca" for federated data discovery in biomedical genomics, and beyond.

Beacon is a basic data discovery protocol issued by the Global Alliance for Genomics and Health (GA4GH). The main goal addressed by version 1 of the Beacon protocol was to test the feasibility of broadly sharing human genomic data, through providing simple "yes" or "no" responses to queries about the presence of a given variant in datasets hosted by Beacon providers. The popularity of this concept has fostered the design of a version 2, that better serves real-world requirements and addresses the needs of clinical genomics research and healthcare, as assessed by several contributing projects and organizations. Particularly, rare disease genetics and cancer research will benefit from new case level and genomic variant level requests and the enabling of richer phenotype and clinical queries as well as support for fuzzy searches. Beacon is designed as a "lingua franca" to bridge data collections hosted in software solutions with different and rich interfaces. Beacon version 2 works alongside popular standards like Phenopackets, OMOP, or FHIR, allowing implementing consortia to return matches in beacon responses and provide a handover to their preferred data exchange format. The protocol is being explored by other research domains and is being tested in several international projects.

The sputum microbiome is distinct between COPD and health, independent of smoking history.

BACKGROUND: Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. METHODS: We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. RESULTS: In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). CONCLUSION: The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

Publisher Correction: Federated discovery and sharing of genomic data using Beacons.

In the version of this article initially published, Lena Dolman's second affiliation was given as Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. The correct second affiliation is Ontario Institute for Cancer Research, Toronto, Ontario, Canada. The error has been corrected in the HTML and PDF versions of the article.

The BioMart community portal: an innovative alternative to large, centralized data repositories.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.

Locus-specific database domain and data content analysis: evolution and content maturation toward clinical use.

Genetic variation databases have become indispensable in many areas of health care. In addition, more and more experts are depositing published and unpublished disease-causing variants of particular genes into locus-specific databases (LSDBs). Some of these databases contain such extensive information that they have become known as knowledge bases. Here, we analyzed 1,188 LSDBs and their content for the presence or absence of 44 content criteria related to database features (general presentation, locus-specific information, database structure) and data content (data collection, summary table of variants, database querying). Our analyses revealed that several elements have helped to advance the field and reduce data heterogeneity, such as the development of specialized database management systems and the creation of data querying tools. We also identified a number of deficiencies, namely, the lack of detailed disease and phenotypic descriptions for each genetic variant and links to relevant patient organizations, which, if addressed, would allow LSDBs to better serve the clinical genetics community. We propose a structure, based on LSDBs and closely related repositories (namely, clinical genetics databases), which would contribute to a federated genetic variation browser and also allow the maintenance of variation data.

An international case-control study of interleukin-4Ralpha, interleukin-13, and cyclooxygenase-2 polymorphisms and glioblastoma risk.

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ralpha, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ralpha (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (-765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ralpha, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ralpha haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ralpha haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development.

Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway.

BACKGROUND: Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS: We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS: We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1 gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS: Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-beta 1-42 and plasma apolipoprotein levels.

The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of beta-amyloid (Abeta) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Abeta 1-42 levels, reinforcing emerging evidence of a connection between lipid and Abeta metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Abeta 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDL-cholesterol (LDL-C) among smokers (P = 0.000055 and P = 0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus non-smokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Abeta and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

Comprehensive genetic evaluation of common E-cadherin sequence variants and prostate cancer risk: strong confirmation of functional promoter SNP.

The E-cadherin gene (CDH1) has been proposed as a prostate cancer (PC) susceptibility gene in several studies. Aberrant protein expression has been related to prognosis and progression in PC. In addition, a functional promoter SNP (rs16260) has been found to associate with PC risk. We performed a comprehensive genetic analysis of CDH1 by using the method of haplotype tagged SNPs in a large Swedish population-based case-control study consisting of 801 controls and 1,636 cases. In addition, Swedish PC families comprising a total of 157 cases sampled for DNA were analyzed for selected SNPs. Seven SNPs, including the promoter SNP rs16260, that captured over 96% of CDH1 haplotype variation were selected as haplotype tagging SNPs and analyzed for associated PC risk. We observed significant confirmation of rs16260 (P=0.003) for cases with a positive family history of PC (FH+) both in an independent case-control population and in PC families. In addition, a common haplotype (HapB, 25%) including the variant allele of rs16260 was associated (P=0.004) with PC risk among FH+ cases. The promoter SNP rs16260 as well as HapB were significantly transmitted to affected offspring in PC families. We report strong confirmation of the association between PC risk in FH+ cases and a functional CDH1 promoter SNP in an independent population. In conjunction with the biological importance of CDH1 our findings encourage further evaluation of genetic variation in CDH1 in relation to PC etiology. Due to the difficulties in replication of genetic association studies, this finding is unusual and novel.

Polymorphisms associated with asthma are inversely related to glioblastoma multiforme.

A reduced risk of primary malignant adult brain tumors is observed among people reporting asthma, hay fever, and other allergic conditions; however, findings may be attributed to prediagnostic effects of tumors or recall bias. To determine whether asthma and allergic condition polymorphisms are inversely related to glioblastoma multiforme (GBM) risk, we conducted a population-based case-control study of 111 GBM patients and 422 controls. We identified five single nucleotide polymorphisms on three genes previously associated with asthma [interleukin (IL)-4RA, IL-13, ADAM33] and one gene associated with inflammation (cyclooxygenase-2). Confirming previous literature, we found that self-reported asthma, eczema, and fever are inversely related to GBM [e.g., asthma odds ratio (OR), 0.64; 95% confidence interval (CI), 0.33-1.25]. In addition, IL-4RA Ser478Pro TC, CC, and IL-4RA Gln551Arg AG, AA are positively associated with GBM (OR, 1.64; 95% CI, 1.05-2.55; 1.61; 95% CI, 1.05-2.47), whereas IL-13 -1,112 CT, TT is negatively associated with GBM (0.56; 95% CI, 0.33-0.96). Each of these polymorphism-GBM associations is in the opposite direction of a corresponding polymorphism-asthma association, consistent with previous findings that self-reported asthmatics and people with allergic conditions are less likely to have GBM than are people who do not report these conditions. Because we used germ line polymorphisms as biomarkers of susceptibility to asthma and allergic conditions, our results cannot be attributed to recall bias or effects of GBM on the immune system. However, our findings are also consistent with associations between IL-4RA, IL-13, and GBM that are independent of their role in allergic conditions.

Lower rate of genomic variation identified in the trans-membrane domain of monoamine sub-class of Human G-Protein Coupled Receptors: the Human GPCR-DB Database.

BACKGROUND: We have surveyed, compiled and annotated nucleotide variations in 338 human 7-transmembrane receptors (G-protein coupled receptors). In a sample of 32 chromosomes from a Nordic population, we attempted to determine the allele frequencies of 80 non-synonymous SNPs, and found 20 novel polymorphic markers. GPCR receptors of physiological and clinical importance were prioritized for statistical analysis. Natural variation and rare mutation information were merged and presented online in the Human GPCR-DB database http://cyrix.cgb.ki.se. RESULTS: The average number of SNPs per 1000 bases of exonic sequence was found to be twice the average number of SNPs per Kilobase of intronic regions (2.2 versus 1.0). Of the 338 genes, 111 were single exon genes, that is, were intronless. The average number of exonic-SNPs per single-exon gene was 3.5 (n = 395) while that for multi-exon genes was 0.8 (n = 1176). The average number of variations within the different protein domain (N-terminus, internal- and external-loops, trans-membrane region, C-terminus) indicates a lower rate of variation in the trans-membrane region of Monoamine GPCRs, as compared to Chemokine- and Peptide-receptor sub-classes of GPCRs. CONCLUSIONS: Single-exon GPCRs on average have approximately three times the number of SNPs as compared to GPCRs with introns. Among various functional classes of GPCRs, Monoamine GPRCs have lower number of natural variations within the trans-membrane domain indicating evolutionary selection against non-synonymous changes within the membrane-localizing domain of this sub-class of GPCRs.

Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer.

PURPOSE: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. EXPERIMENTAL DESIGN: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. RESULTS: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. CONCLUSIONS: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.

Complex SNP-related sequence variation in segmental genome duplications.

There is uncertainty about the true nature of predicted single-nucleotide polymorphisms (SNPs) in segmental duplications (duplicons) and whether these markers genuinely exist at increased density as indicated in public databases. We explored these issues by genotyping 157 predicted SNPs in duplicons and control regions in normal diploid genomes and fully homozygous complete hydatidiform moles. Our data identified many true SNPs in duplicon regions and few paralogous sequence variants. Twenty-eight percent of the polymorphic duplicon sequences we tested involved multisite variation, a new type of polymorphism representing the sum of the signals from many individual duplicon copies that vary in sequence content due to duplication, deletion or gene conversion. Multisite variations can masquerade as normal SNPs when genotyped. Given that duplicons comprise at least 5% of the genome and many are yet to be annotated in the genome draft, effective strategies to identify multisite variation must be established and deployed.

Further evidence for role of a promoter variant in the TNFRSF6 gene in Alzheimer disease.

The tumor necrosis factor receptor superfamily, member 6 gene (TNFRSF6) is situated on chromosome 10q, near the region indicated in several AD linkage studies. In a previous study a significant association was found between a promoter variant within the TNFRSF6 gene and Alzheimer disease (AD). To further investigate the TNFRSF6 region, 34 SNPs within 180 kb were first genotyped in an exploratory set of 121 early-onset dementia cases and 152 controls in order to establish the extent of linkage disequilibrium (LD) and the major haplotypes in the region. This analysis showed that the LD was clustered in two large blocks within each of which a limited number of haplotypes represented most of the diversity. Haplotype tagging markers were chosen and genotyped in an additional 204 late onset AD cases and 177 controls. Tests of association were performed for single markers for case/control status and for a quantitative measure of cognitive ability [Mini-Mental State Examination (MMSE) scores] within cases only. The previously associated marker, located in the promoter of TNFRSF6, now gave significant association with cognitive status in the Scottish early-onset dementia samples (p = 0.005) with the strongest signals being evident in the APOE-e4 carrier subgroup, thus providing a second independent positive result for this marker. The same marker was also significantly associated with cognitive performance in the Swedish APOE-e4 carriers (p = 0.014), providing a third independent signal. Association analysis was also performed using the major haplotypes in the region, employing both case/control status and MMSE scores. The haplotype analysis did not give further significant findings. These results together with previous data suggest that a promoter marker in TNFRSF6 plays a moderate but demonstrable role in AD etiology.

A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.