A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5×10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Five-year course and outcome of dysthymic disorder: A prospective, naturalistic follow-up study.

OBJECTIVE: There have been few naturalistic follow-up studies of dysthymic disorder. This study describes the 5-year course and outcome of dysthymic disorder. METHOD: The authors conducted a prospective, longitudinal follow-up study of 86 outpatients with early-onset dysthymic disorder and 39 outpatients with episodic major depressive disorder. Follow-ups, conducted 30 and 60 months after entry into the study, rated patients on the Longitudinal Interval Follow-Up Evaluation and the Modified Hamilton Rating Scale for Depression. RESULTS: The estimated 5-year recovery rate from dysthymic disorder was 52.9%. Among patients who recovered, the estimated risk of relapse was 45.2% during a mean of 23 months of observation. Patients with dysthymic disorder spent approximately 70% of the follow-up period meeting the full criteria for a mood disorder. During the course of the follow-up the patients with dysthymic disorder exhibited significantly greater levels of symptoms and lower functioning and were significantly more likely to attempt suicide and to be hospitalized than were patients with episodic major depressive disorder. Finally, among patients with dysthymic disorder who had never experienced a major depressive episode before entry into the study, the estimated risk of having a first lifetime major depressive episode was 76.9%. CONCLUSIONS: Dysthymic disorder is a chronic condition with a protracted course and a high risk of relapse. In addition, almost all patients with dysthymic disorder eventually develop superimposed major depressive episodes. Although patients with dysthymic disorder tend to show mild to moderate symptoms, from a longitudinal perspective, the condition is severe.

Thirty-month naturalistic follow-up study of early-onset dysthymic disorder: course, diagnostic stability, and prediction of outcome.

Dysthymic disorder (DD) is defined and distinguished from major depressive disorder (MDD) largely on the basis of its course. Surprisingly, however, there have been few prospective, longitudinal studies of the naturalistic course of DD. This article reports the major findings from a prospective, longitudinal 30-month follow-up study of 86 outpatients with early-onset DD (EOD) and 39 outpatients with episodic MDD. Follow-up assessments included the Longitudinal Interval Follow-Up Evaluation and Hamilton Rating Scale for Depression. Compared with patients with episodic MDD, patients with EOD exhibited less improvement from the baseline evaluation and were more symptomatic at follow-up. Only 39% of patients with EOD recovered from DD during the follow-up period. The diagnosis of DD was fairly stable, with 52% of the EOD group meeting full criteria for DD at follow-up. These data provide prospective confirmation of the chronic course of DD.

30-month stability of personality disorder diagnoses in depressed outpatients.

OBJECTIVE: This study examined the 30-month stability of axis II conditions. METHOD: One hundred eight depressed outpatients received comprehensive, semistructured personality disorder assessments at baseline and at follow-up. RESULTS: The diagnostic stability of personality disorders ranged from low to moderate at the categorical level and was generally moderate at the dimensional level. Most disorders exhibited good discriminant validity, in that the association between a disorder at baseline and at follow-up was greater than the associations between that disorder at baseline and the other 11 axis 11 disorders at follow-up. Two variables, sex and lifetime history of substance abuse or dependence, were significantly related to change in level of personality disorder features over time. CONCLUSIONS: Personality disorders have low to moderate stability over a 30-month period in depressed outpatients.

Social adjustment in dysthymia, double depression and episodic major depression.

We contrasted the overall social functioning of pure dysthymics, double depressives, episodic major depressives and normal controls using both interview and self-report measures of social functioning and depression. In addition, we used hierarchical multiple regression to assess the differential impact of several variables (comorbid personality, anxiety and substance use disorders, life stress, duration of dysthymia and severity of depressive symptomatology) on social functioning in the dysthymics and double depressives. Participants included 41 outpatients with early-onset dysthymia alone, 56 outpatients with early-onset dysthymia and concurrent major depression, 45 outpatients with episodic major depression and 45 normal controls. All 3 patient groups were found to be significantly more impaired than normal controls in overall functioning, as well as in every specific role area. Double depression was found to be particularly impairing, both in overall functioning and in every specific role area. In dysthymic patients with and without concurrent major depression, current depressive symptomatology is the strongest predictor of impairment. Taken together, these data suggest that chronic, low-grade depressive symptoms and acute, moderate depressive symptoms have similar, significant and additive effects on social adjustment.