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A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population.

ABSTRACT: Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N?=?65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P?=?2.16?×?10-208, OR?=?1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P?=?2.17?×?10-17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P???10-5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

SUBMITTER: Nudel R

PROVIDER: S-EPMC6848113 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population.

Nudel Ron R Wang Yunpeng Y Appadurai Vivek V Schork Andrew J AJ Buil Alfonso A Buil Alfonso A Agerbo Esben E Bybjerg-Grauholm Jonas J Børglum Anders D AD Daly Mark J MJ Mors Ole O Hougaard David M DM Mortensen Preben B PB Werge Thomas T Nordentoft Merete M Thompson Wesley K WK Benros Michael E ME

Translational psychiatry 20191111 1

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationw ...[more]

PMID: 31712607

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Project description:ImportanceIndividuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity.ObjectivesTo undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice.Design, setting, and participantsThis population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018.Main outcomes and measuresDanish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated.ResultsA total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years).Conclusions and relevanceComorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

Project description:Importance:The association of mental disorders with premature mortality published in the Global Burden of Disease (GBD) studies has been underestimated because these analyses have recommended using only a small number of mental disorders as causes of death to estimate years of life lost (YLL). Alternative methods have been introduced, such as estimating life-years lost (LYL), to compare individuals with mental disorders with the general population. Objectives:To generate register-based YLL and LYL estimates and to use these measurement methods to assess the association of specific mental disorders with premature mortality. Design, Setting, and Participants:This population-based cohort study included all persons with and without mental disorders aged 0 to 94 years who were living in Denmark between January 1, 2000, and December 31, 2015. Data were analyzed from January to December 2019. Main Outcomes and Measures:Danish health registers were used to identify mental disorder diagnoses, dates of death, and causes of death. The YLLs were estimated for the set of mental health-associated causes of death, and all-cause and cause-specific LYLs were estimated for 18 specific mental disorders and 3 broad categories of mental disorders that were recommended for use in the GBD studies. The association between the number of comorbid mental disorders (divided into categories of persons with ≥1 type of disorder, ≥2 types of disorders, ≥3 types of disorders, and ≥4 types of disorders) and LYL estimates was also examined. Results:A total of 6 989 627 individuals (3 481 219 male persons [49.8%] and 3 508 408 female persons [50.2%]; mean [SD] age at study enrollment, 32.2 [24.4] years) were followed up for a total of 85 911 461 person-years. The YLL rates per 100 000 person-years were highest for alcohol use disorder (for male individuals, 568.7 [95% CI, 564.4-572.7]; for female individuals, 155.5 [95% CI, 153.5-157.9]) and suicide (for male individuals, 590.1 [95% CI, 583.8-596.5]; for female individuals, 202.3 [95% CI, 198.5-206.4]). Although only 3 of 18 mental and substance use disorders could be associated with YLL, all mental disorders were associated with shorter life expectancies when LYL was used for measurement. Male and female individuals diagnosed with any mental disorder had life expectancies that were shorter by 11.2 years (95% CI, 11.1-11.3 years) and 7.9 years (95% CI, 7.8-8.0 years), respectively, and remaining life expectancy decreased further among those with comorbid mental disorders. Drug use disorders were associated with the highest excess LYL estimates; however, common mental disorders, such as depressive and anxiety disorders, were also associated with substantial premature mortality. Conclusions and Relevance:Mental disorders were observed to be associated with reductions in life expectancy. This finding provides a foundation for future intervention programs designed to reduce the differential mortality gap associated with mental disorders. Register-based studies allow the calculation of precise individual-level YLLs and LYLs, and both measurement methods are informative for health care planning. Compared with YLL, the novel LYL measurement approach may more precisely capture the association of mental disorders with premature mortality and facilitates the exploration of comorbidity and specific causes of death in individuals with mental disorders.

Dataset Information

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population.

Publications

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population.

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