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The Genetics of Morbidity and Survival in Response to Significant Life Stressors

Periodic Reporting for period 2 - StressGene (The Genetics of Morbidity and Survival in Response to Significant Life Stressors)

Reporting period: 2018-12-01 to 2020-05-31

Most humans are at some point in their lives exposed to significant life stressors or trauma. Significant life stressors such as death of loved ones, being diagnosed with a life-threatening illness, and exposure to natural disasters or violence – are well-documented risk factors of ill health, disability and premature mortality. Why some individuals remain healthy while others remiss to adverse symptoms, disease or death after exposure to such life stressors remains unclear. The overarching aim of the StressGene program is to advance current understanding of the potential genetic contribution to varying trajectories of health following exposure to significant life stressors.

The program leverages the nationwide Icelandic and Swedish registries together with the unique genetic and genealogical resources at deCODE Genetics, to further elucidate the association between life stressors or trauma and subsequent risk of various diseases as well as the impact of sequence variants on individual variation in morbidity and mortality after such stressful exposures, including after loss of a family member and receiving a cancer diagnosis. We will further seek to identify sequence variants associated with variation in symptoms of posttraumatic stress disorder (PTSD) in two highly traumatized cohorts: the SAGA cohort of 30.000 Icelandic women with high lifetime prevalence of violence exposure, as well as a cohort of 5.000 Swedes exposed to the 2004 SA-Asian Tsunami.
While data collection from the Swedish Tsunami cohort (N=14.700) is ongoing, the recruitment of 31.811 female participants to the SAGA cohort was completed on July 1st 2019. Statistical analyses are being conducted and record linkage to the genetic database at deCODE Genetics. Covering roughly one-third of the national female population (aged 18-69 years), preliminary results show that the participants represent the background population in terms of age, education, income and residency. The results further indicate high lifetime prevalence of various trauma, including exposure to violence, and high rates of PTSD symptomology in clinically significant range. Further statistical analyses and reporting of these results will be executed during the latter half of this program.
Using the unique registries in Sweden and Iceland, this program has already made new discoveries on the impact of significant life stressors on population health. Using the unique Icelandic Genealogic database (Íslendingabók), we found that mothers who had lost a child were compared to their sisters (who were also mothers but did not experience child loss) at increased risk of premature mortality (death before the age of 50) across the 200 years of follow-up (Valdimarsdóttir et al., eLife 2019). Statistical analyses of the genetic contribution to variations in parental survival following child loss are now being executed.
Using Swedish nationwide registry resources, we have further demonstrated how individuals diagnosed with stress-related disorders (e.g. posttraumatic stress disorder or adjustment disorder) run, compared to their siblings, increased risks of several autoimmune diseases (Song et al., JAMA 2018), most cardiovascular diseases (Song et al., BMJ 2019), and all tested life-threatening infections (Song et al., BMJ 2019).
Virtually everyone is at some point in their life exposed to significant life stressors or trauma. Physical or sexual violence against women is highly prevalent worldwide, with approximately one in every three women being exposed at some point during their lives. Moreover, during the last decade, 200 million people were annually affected by natural disasters worldwide.
This program brings together leading scientists in stress research, psychiatric epidemiology and genetics and leverages uniquely comprehensive population-based resources in two different countries to further elucidate the impact of significant life stressors on health and to address the potential genetic basis of varying health outcomes after exposure to significant life stressors. Improved knowledge from this comprehensive research program for early identification of vulnerable individuals is paramount for cost-effective interventions, psychological or pharmacological, targeting reduced risks of morbidity in affected populations. Thus, the findings of the proposed studies may have significant implications for biological characterization of individuals at risk of adverse health outcomes after exposure to trauma as well as on the development of clinical- and public health interventions targeting the large populations that inevitably will continue to be exposed to such events.
The main milestones and results reached so far are the following:
Work Package 1: To elucidate novel associations between significant life stressors and diseases and identify genetic variants associated with varying risks of major disease and mortality in response to significant life stressors.
1) Record linkage of the nationwide registers in Iceland for the project are currently close to completion. With data from the Icelandic Genealogic database (Íslendingabók), we have been able to pursue studies of parental mortality following child loss. Using data from more than 47 thousand parents who lost a child during the past 200 years, we found that mothers who had endured such an experienced were compared to their sisters (who were also mothers but did not experience child loss) at increased risk of premature mortality (death before the age of 50) across the 200 years of follow-up (Valdimarsdóttir et al., eLife 2019). Statistical analyses of the genetic contribution to variations in parental survival following child loss are now being executed.
2) We further leveraged ongoing projects in Swedish registry resources to discovered new relevant disease-related phenotypes associated with stress and trauma, and to be further pursued in ongoing genetic studies. These studies have already yielded several high-impact publications. Stress-related disorders are a group of psychiatric disorders (ICD-10: F43) that are directly associated with exposure to traumatic events (e.g. acute- or posttraumatic stress disorders) or a significant life change (adjustment disorder). We identified all individuals in Sweden diagnosed with stress-related disorders (N>100.000) and used elaborate population- and sibling designs to estimate associations to subsequent major disease risks, while controlling for important confounders such as psychiatric and somatic comorbidities and family history of disease. We found that individuals who received a diagnosis of stress-related disorder were, compared to their siblings and population-controls, at increased subsequent risk of several autoimmune diseases (Song et al., JAMA 2018), most cardiovascular diseases (Song et al., BMJ 2019), all tested life-threatening infections (Song et al., BMJ 2019) and neurodegenerative disease (Song et al., in press JAMA Neurology).

Work Package 2: To identify genetic variants associated with variation in symptoms and trajectories of posttraumatic stress disorder after exposure to trauma.
1) The recruitment of 31.811 participants to the SAGA cohort was completed on July 1st 2019 – 12 months ahead of schedule according to the DoA. Statistical analyses are being conducted and record linkage with the genetic database at deCODE Genetics. Covering roughly one-third of the national female population (aged 18-69 years), preliminary results show that the participants represent the background population in terms of age, education, income and residency. The results further indicate high lifetime prevalence of various trauma, including almost 40% lifetime exposure to violence, and more than one-fifth of the women reaching a threshold suggestive of PTSD. Further statistical analyses and reporting of these results will be executed during the latter half of this program.
2) The data collection of the Swedish Tsunami Cohort is ongoing and until now around 6000 survivors have been contacted.
As described in 1.2 we have already made significant contribution to the literature in this area. These contributions are described above and have been published in the following high impact publications:
Song H, Fang F, Tomasson G, Arnberg FK, Mataix-Cols D, Fernández de la Cruz L, Almqvist C, Fall K, Valdimarsdóttir UA. Association of Stress-Related Disorders With Subsequent Autoimmune Disease. JAMA. 2018 Jun 19;319(23):2388-2400. doi: 10.1001/jama.2018.7028.

Song H, Fang F, Arnberg FK, Mataix-Cols D, Fernández de la Cruz L, Almqvist C, Fall K, Lichtenstein P, Thorgeirsson G, Valdimarsdóttir UA. Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study. BMJ. 2019 Apr 10;365:l1255. doi: 10.1136/bmj.l1255.

Song H, Fall K, Fang F, Erlendsdóttir H, Lu D, Mataix-Cols D, Fernández de la Cruz L, D'Onofrio BM, Lichtenstein P, Gottfreðsson M, Almqvist C, Valdimarsdóttir UA. Stress related disorders and subsequent risk of life threatening infections: population based sibling controlled cohort study. BMJ. 2019 Oct 23;367:l5784. doi: 10.1136/bmj.l5784.

Valdimarsdóttir UA, Lu D, Lund SH, Fall K, Fang F, Kristjánsson Þ, Guðbjartsson D, Helgason A, Stefánsson K. The mother's risk of premature death after child loss across two centuries. Elife. 2019 Nov 12;8. pii: e43476. doi: 10.7554/eLife.43476.

Prospective work includes:
Work-package 1:
- Statistical analyses of the Icelandic register data to capture severe health outcomes following significant life stressors, including psychiatric disorders and cardiovascular events.
- Record linkage of the stress/trauma-related, register-based phenotypes to the genetic database at deCODE Genetics.
- Genome-wide association studies of stress/trauma-related phenotypes.
- Polygenic risk score analyses of stress/trauma-related phenotypes.
- Manuscript writing, submission of papers.
Work-package 2:
SAGA Cohort:
- Statistical analyses of the SAGA cohort, including quantification of symptoms of posttraumatic stress and resilience after trauma (ongoing)
- Record-linkage of these trauma-related phenotypes to the deCODE Genetics database.
- Invitation to participants to complement with genetic data (autumn 2020)
- Genome wide association and polygenic risk score analyses, manuscript writing and submission (2021-22).
Tsunami cohort:
- Data collection completed (mid 2021)
- Genotyping (2021)
- Analyses of long-term posttraumatic stress symptoms after a massive natural disaster (2021)
- GWAS and polygenic risk score analyses, manuscript writing and submission (2021-22)