A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828=53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10-199), and thrombosis ORrs505922 1.33, p=2.2 × 10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26 × 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 × 10-23, lupus OR 0.84, p=3.97 × 10-06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10-13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

The Association Between Parental Depression and Child Psychosocial Intervention Outcomes: Directions for Future Research.

Recent studies suggest that parental depressive symptoms may affect a child's ability to benefit from interventions for anxiety and depression. This article reviews the current literature, suggesting that, when parents experience current depressive symptoms, children are less likely to benefit from psychosocial interventions for anxiety and depression. Opportunities for future research are discussed, including moderators and mechanisms of the association between parental depressive symptoms and child intervention outcomes.

Effect of Internet-based Cognitive Behavioral Humanistic and Interpersonal Training vs. Internet-based General Health Education on Adolescent Depression in Primary Care: A Randomized Clinical Trial.

IMPORTANCE: Although 13-20% of American adolescents experience a depressive episode annually, no scalable primary care model for adolescent depression prevention is currently available. OBJECTIVE: To study whether CATCH-IT (Competent Adulthood Transition with Cognitive Behavioral Humanistic and Interpersonal Training) reduces the hazard for depression in at-risk adolescents identified in primary care, as compared to a general health education attention control (HE). DESIGN: The Promoting AdolescenT Health (PATH) study compares CATCH-IT and HE in a phase 3 single-blind multicenter randomized attention control trial. Participants were enrolled from 2012 to 2016 and assessed at 2, 6, 12, 18, and 24 months post-randomization. SETTING: Primary care. PARTICIPANTS: Eligible adolescents were 13-18 years with subsyndromal depression and/or history of depression and no current depression diagnosis or treatment. Of 2,250 adolescents screened for eligibility, 446 participants completed the baseline interview and 369 were randomized into CATCH-IT (n=193) and HE (n=176). INTERVENTIONS: CATCH-IT is a 20-module (15 adolescent modules, 5 parent modules) online psychoeducation course that includes a parent program, supported by three motivational interviews. MAIN OUTCOMES AND MEASURES: Time-to-event for depressive episode; depressive symptoms at 6 months. RESULTS: Mean age was 15.4 years, and 68% were female; 28% had both a past episode and subsyndromal depression; 12% had a past episode only, 59% had subsyndromal depression only, and 1% had borderline subsyndromal depression. The outcome of time-to-event favored CATCH-IT but was not significant with intention-to-treat analyses (N=369; unadjusted HR=0.59; 95% CI 0.27, 1.29; p=0.18; adjusted HR=0.53; 95% CI 0.23, 1.23, p=0.14). Adolescents with higher baseline CES-D10 scores showed a significantly stronger effect of CATCH-IT on time-to-event relative to those with lower baseline scores (p=0.04). For example, for a CES-D10 score of 15 (significant sub-syndromal depression), HR=0.20 (95% CI 0.05, 0.77), compared to CES-D10 of 5 (no sub-syndromal depression), HR=1.44 (95% CI, 0.41, 5.03). In both CATCH-IT and HE groups, depression symptoms declined and functional scores increased. CONCLUSIONS AND RELEVANCE: CATCH-IT may be better than HE for preventing depressive episodes for at-risk adolescents with sub-syndromal depression. CATCH-IT may be a scalable approach to prevent depressive episodes in adolescents in primary care.

A pilot study of a chiropractic intervention for management of chronic myofascial temporomandibular disorder.

BACKGROUND: Temporomandibular pain has multiple etiologies and a range of therapeutic options. In this pilot study, the authors assessed the feasibility of conducting a larger trial to evaluate chiropractic treatment of temporomandibular disorders (TMDs). METHODS: The authors assigned 80 participants randomly into one of the following four groups, all of which included a comprehensive self-care program: reversible interocclusal splint therapy (RIST), Activator Method Chiropractic Technique (AMCT) (Activator Methods International, Phoenix), sham AMCT and self-care only. They made assessments at baseline and at month 2 and month 6, including use of the Research Diagnostic Criteria for Temporomandibular Disorders. RESULTS: The authors screened 721 potential participants and enrolled 80 people; 52 participants completed the six-month assessment. The adjusted mean change in current pain over six months, as assessed on the 11-point numerical rating scale, was 2.0 (95 percent confidence interval, 1.1-3.0) for RIST, 1.7 (0.9-2.5) for self-care only, 1.5 (0.7-2.4) for AMCT and 1.6 (0.7-2.5) for sham AMCT. The authors also assessed bothersomeness and functionality. CONCLUSIONS: The authors found the study design and methodology to be manageable. They gained substantial knowledge to aid in conducting a larger study. AMCT, RIST and self-care should be evaluated in a future comparative effectiveness study. PRACTICAL IMPLICATIONS: This pilot study was a necessary step to prepare for a larger study that will provide clinicians with information that should be helpful when discussing treatment options for patients with TMD.