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

Significant life stressors – including 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 this research 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 registries of major diseases and mortality covering the whole Icelandic nation (N=330.000) and the unique genetic- and genealogical resources at deCODE Genetics to perform genome-wide association studies (GWAS) on the varying risks of overall mortality and major diseases (including psychiatric disorders and cardiovascular disease) after loss of a family member or after 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. This research program represents the first major attempt to address the potential genetic basis of varying somatic health outcomes after exposure to significant life stressors and, to our knowledge, one of the first comprehensive GWAS on PTSD in European populations.

Virtually everyone is at some point in their life exposed to significant life stressors or trauma; the knowledge gained from this comprehensive research program may facilitate early identification and refined, personalized interventions for the most vulnerable individuals of the large populations worldwide that inevitably will continue to be exposed to trauma.

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 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.