Phenome-wide Association Analysis Research Articles

Evolutionary medical insights into the SARS-CoV-2 pandemic.

The author apply concepts and tools from evolutionary medicine to understanding the SARS-CoV-2 pandemic. The pandemic represents a mismatched conflict, with dynamics and pathology apparently driven by three main factors: (i) bat immune systems that rely on low inflammation but high efficacy of interferon-based defenses; (ii) viral tactics that differentially target the human interferon system, leading to substantial asymptomatic and pre-symptomatic transmission; and (ii) high mortality caused by hyper-inflammatory and hyper-coagulatory phenotypes, that represent dysregulated tradeoffs whereby collateral immune-induced damage becomes systemic and severe. This framework can explain the association of mortality with age (which involves immune life-history shifts towards higher inflammation and coagulation and reduced adaptive immunity), and sex (since males senesce faster than females). Genetic-risk factors for COVID-19 mortality can be shown, from a phenome-wide association analysis of the relevant SNPs, to be associated with inflammation and coagulation; the phenome-wide association study also provides evidence, consistent with several previous studies, that the calcium channel blocking drug amlodipine mediates risk of mortality. Lay Summary: SARS-CoV-2 is a bat virus that jumped into humans. The virus is adapted to bat immune systems, where it evolved to suppress the immune defenses (interferons) that mammals use to tell that they are infected. In humans, the virus can apparently spread effectively in the body with a delay in the production of symptoms and the initiation of immune responses. This delay may then promote overactive immune responses, when the virus is detected, that damage the body as a side effect. Older people are more vulnerable to the virus because they are less adapted to novel infectious agents, and invest less in immune defense, compared to younger people. Genes that increase risk of mortality from SARS-CoV-2 are functionally associated with a drug called amlodipine, which may represent a useful treatment.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Childhood intelligence attenuates the association between biological ageing and health outcomes in later life

The identification of biomarkers that discriminate individual ageing trajectories is a principal target of ageing research. Some of the most promising predictors of biological ageing have been developed using DNA methylation. One recent candidate, which tracks age-related phenotypes in addition to chronological age, is ‘DNAm PhenoAge’. Here, we performed a phenome-wide association analysis of this biomarker in a cohort of older adults to assess its relationship with a comprehensive set of both historical, and contemporaneously-measured, phenotypes. Higher than expected DNAm PhenoAge compared with chronological age, known as epigenetic age acceleration, was found to associate with a number of blood, cognitive, physical fitness and lifestyle variables, and with mortality. Notably, DNAm PhenoAge, assessed at age 70, was associated with cognitive ability at age 11, and with educational attainment. Adjusting for age 11 cognitive ability attenuated the majority of the cross-sectional later-life associations between DNAm PhenoAge and health outcomes. These results highlight the importance of early life factors on healthy older ageing.

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.MethodsPublished and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.ResultsThe PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable.ConclusionsGenetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

Association between major depressive disorder and multiple disease outcomes: a phenome-wide Mendelian randomisation study in the UK Biobank.

Depression affects all aspects of an individual's life but evidence relating to the causal effects on health is limited. We used information from 337,536 UK Biobank participants and performed hypothesis-free phenome-wide association analyses between major depressive disorder (MDD) genetic risk score (GRS) and 925 disease outcomes. GRS-disease outcome associations passing the multiple-testing corrected significance threshold (P < 1.9 × 10-3) were followed by Mendelian randomisation (MR) analyses to test for causality. MDD GRS was associated with 22 distinct diseases in the phenome-wide discovery stage, with the strongest signal observed for MDD diagnosis and related co-morbidities including anxiety and sleep disorders. In inverse-variance weighted MR analyses, MDD was associated with several inflammatory and haemorrhagic gastrointestinal diseases, including oesophagitis (OR 1.32, 95% CI 1.18-1.48), non-infectious gastroenteritis (OR 1.25, 95% CI 1.06-1.48), gastrointestinal haemorrhage (OR 1.26, 95% CI 1.11-1.43) and intestinal E.coli infections (OR 3.24, 95% CI 1.74-6.02). Signals were also observed for symptoms/disorders of the urinary system (OR 1.36, 95% CI 1.19-1.56), asthma (OR 1.23, 95% CI 1.06-1.44), and painful respiration (OR 1.28, 95% CI 1.14-1.44). MDD was associated with disorders of lipid metabolism (OR 1.22, 95% CI 1.12-1.34) and ischaemic heart disease (OR 1.30, 95%CI 1.15-1.47). Sensitivity analyses excluding pleiotropic variants provided consistent associations. Our study indicates a causal link between MDD and a broad range of diseases, suggesting a notable burden of co-morbidity. Early detection and management of MDD is important, and treatment strategies should be selected to also minimise the risk of related co-morbidities.

From the Editor’s Desk: September 2019

From the Editor’s Desk: September 2019

Association of APOL1 Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.

Parent of origin genetic effects on methylation in humans are common and influence complex trait variation

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.

SA33 - VARIABILITY IN EXPRESSION OF TMEM163 IN BRAIN CORTEX IS ASSOCIATED WITH RESILIENCE TO MULTIPLE BRAIN DAMAGE PHENOTYPES IN A BIOBANK POPULATION

Background Resilience to brain damage describes the imperfect correlation between clinical symptoms and the extent of brain injury, whether traumatic, degenerative, or vascular in origin. DNA samples linked to electronic medical records (biobanks) offer unique opportunities to identify genes that underlie multiple brain resilience phenotypes. We use Traumatic Brain Injury (TBI) as our discovery phenotype, since over 8 million Americans sustain a TBI annually, and the pathology underlying TBI is hypothesized to overlap that of other neurological diseases, ranging from persistent headache to dementia. Methods We report the first GWAS of TBI risk, conducted in the Vanderbilt University Biobank, BioVU, which includes >270,000 patients. Results from single SNP analyses can be difficult to interpret and pay a heavy multiple testing burden. We therefore applied a gene-based tool, PrediXcan, to predict gene expression levels in 9155 European-ancestry BioVU patients from genome-wide genotype data in the target sample (BioVU) and a reference transcriptome dataset (GTEx). We tested 11005 genes in whole blood and 9164 genes in brain cortex for association with TBI defined by CDC criteria as one or more ICD codes for ‘Cerebral laceration and contusion’, ‘Concussion’, ‘Intracranial hemorrhage following injury’, ‘Skull fracture’, and ‘Other intracranial injury’. Analyses were adjusted for sex, age (at first TBI or at last ICD code in the medical record), and principal components 1–3. Genes significantly associated with TBI were tested for association with 1309 phenotype codes in a Phenome-Wide Association Analysis (PheWAS). Results TBI was diagnosed in 503 of 9155 patients. The median age at first TBI was 51.7 years, 6.8% of patients were Discussion Our analyses suggest that TMEM163 expression in cortex is associated with resilience to multiple types of brain damage. Further research is warranted to disentangle the complex temporal and potentially confounding relationships between phenotypes.

Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease.

Diverticular disease is common and morbid. Treatments are limited due to poor understanding of its pathophysiology. To elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) in the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease, 39 of them novel. Using DEPICT, we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that play a role in vascular and mesenchymal biology. Genes in these associated loci play roles in immunity, extracellular matrix biology, cell adhesion, membrane transport, and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses establish the genomic landscape of diverticular disease.

Association between Depression and Multiple Disease Outcomes: A Phenome-Wide Mendelian Randomization Study in the UK Biobank

Background: Depression has profound effects on an individual's life but evidence relating to the causal effects on health is limited. Previous studies examining the relationship between depression and disease are largely observational making causal prediction challenging due to confounding and reverse causation. The aim of this study is to establish genetic evidence for a causal association between depression and a range of disease outcomes. Methods We performed hypothesis-free phenome-wide association analyses of depression and 925 disease outcomes based on linked data on hospitalisations and mortality from 337,536 participants in the UK Biobank. Depression was instrumented by weighted genetic risk score (GRS) derived from 44 depression variants, with sensitivity analyses using restricted 17 variant score. GRSs-disease outcome associations passing the multiple-testing corrected significance threshold (P<1.9 x 10-3) were followed by Mendelian randomization (MR) analyses. Findings: Depression GRS was associated with 42 disease outcomes in the phenome-wide discovery stage, and inverse-variance weighted (IVW) MR analyses supported a possible causal link between depression and 25 of these disease outcomes. The strongest signal was observed for depression diagnosis (Pdiscovery<8·4 x 10-14), and related co-morbidities including anxiety (Pdiscovery= 3·0 x 10-7; MR IVW OR 1·89, 95%CI 1·50 to 2·38), and sleep disorders (Pdiscovery=1·8 x 10-4; OR 1·59, 95%CI 1·27 to 1·98). Further genetic evidence for a possible causal effect of depression was seen for inflammatory and haemorrhagic gastrointestinal diseases, including diseases of the oesophagus (Pdiscovery=3·0 x10-7; OR 1·30, 95%CI 1·17 to 1·46), non-infectious gastroenteritis (Pdiscovery=1·2x10-3; OR 1·25, 95%CI 1·06 to 1·48), and gastrointestinal haemorrhage (Pdiscovery=3·8x10-4; OR 1·26, 95%CI 1·11 to 1·43). Signals were also observed for symptoms/disorders of the urinary system (Pdiscovery=1·7 x 10-5; OR 1·36, 95%CI 1·19 to 1·56), asthma (Pdiscovery =3·9 x 10-4; OR 1·23, 95%CI 1·06 to 1·44), and painful respiration (Pdiscovery =4·0 x10-7; OR1·28, 95%CI 1·14 to 1·44). Depression was also causally linked with disorders of lipid metabolism (Pdiscovery=3·8x10-5; OR 1·22, 95%CI 1·12 to 1·34) and ischaemic heart disease (Pdiscovery=3·3x10-7, OR 1·30, 95CI 1·15 to 1·47). Seven variants showed evidence for pleiotropy, but sensitivity analyses excluding these variants provided consistent associations. Interpretation Our study indicated a causal link between depression and a broad range of diseases, suggesting a notable burden of co-morbidity. Early detection and management of depression is important, but treatment strategies should be selected to also minimize the risk of related co-morbidities. Funding: Australian Research Training Program. Conflict of interest: The authors have declared that no competing interest exist. Ethical Approval Statement: We have used an open-access database, called UK biobank, to generate our finding and conclusion. UK Biobank has approval from the North West Multi-centre Research Ethics committee, Patient Information Advisory Group, and Community Health Index Advisory Group (http://www.ukbiobank.ac.uk/ethics/). Each participant provided written consent during the recruitment phase of the project (http://www.ukbiobank.ac.uk/wp-content/uploads/2011/06/Consent_form.pdf?phpMyAdmin=trmKQlYdjjnQIgJ%2CfAzikMhEnx6).

Association between borderline dysnatremia and mortality insight into a new data mining approach

BackgroundEven small variations of serum sodium concentration may be associated with mortality. Our objective was to confirm the impact of borderline dysnatremia for patients admitted to hospital on in-hospital mortality using real life care data from our electronic health record (EHR) and a phenome-wide association analysis (PheWAS).MethodsRetrospective observational study based on patient data admitted to Hôpital Européen George Pompidou, between 01/01/2008 and 31/06/2014; including 45,834 patients with serum sodium determinations on admission. We analyzed the association between dysnatremia and in-hospital mortality, using a multivariate logistic regression model to adjust for classical potential confounders. We performed a PheWAS to identify new potential confounders.ResultsHyponatremia and hypernatremia were recorded for 12.0% and 1.0% of hospital stays, respectively. Adjusted odds ratios (ORa) for severe, moderate and borderline hyponatremia were 3.44 (95% CI, 2.41–4.86), 2.48 (95% CI, 1.96–3.13) and 1.98 (95% CI, 1.73–2.28), respectively. ORa for severe, moderate and borderline hypernatremia were 4.07 (95% CI, 2.92–5.62), 4.42 (95% CI, 2.04–9.20) and 3.72 (95% CI, 1.53–8.45), respectively. Borderline hyponatremia (ORa = 1.57 95% CI, 1.35–1.81) and borderline hypernatremia (ORa = 3.47 95% CI, 2.43–4.90) were still associated with in-hospital mortality after adjustment for classical and new confounding factors identified through the PheWAS analysis.ConclusionBorderline dysnatremia on admission are independently associated with a higher risk of in-hospital mortality. By using medical data automatically collected in EHR and a new data mining approach, we identified new potential confounding factors that were highly associated with both mortality and dysnatremia.

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

Biobanks and national registries represent a powerful tool for genomic discovery, but rely on diagnostic codes that can be unreliable and fail to capture relationships between related diagnoses. We developed an efficient means of conducting genome-wide association studies using combinations of diagnostic codes from electronic health records for 10,845 participants in a biobanking program at two large academic medical centers. Specifically, we applied latent Dirichilet allocation to fit 50 disease topics based on diagnostic codes, then conducted a genome-wide common-variant association for each topic. In sensitivity analysis, these results were contrasted with those obtained from traditional single-diagnosis phenome-wide association analysis, as well as those in which only a subset of diagnostic codes were included per topic. In meta-analysis across three biobank cohorts, we identified 23 disease-associated loci with p < 1e-15, including previously associated autoimmune disease loci. In all cases, observed significant associations were of greater magnitude than single phenome-wide diagnostic codes, and incorporation of less strongly loading diagnostic codes enhanced association. This strategy provides a more efficient means of identifying phenome-wide associations in biobanks with coded clinical data.

Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes.

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have been implicated, independently, in type 2 diabetes (T2D) but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB), and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA) in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, β-Klotho, FGFR4, HNF4α, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were < 200 mg/mL and FGF21 > 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.