Risk Factors for Syncope Associated With Multigenerational Relatives With a History of Syncope.

Importance: Reflex syncope is the major cause of transient loss of consciousness, which affects one-third of the population, but effective treatment for individuals with severe syncope is lacking. Better understanding of reflex syncope predisposition may offer new therapeutic solutions. Objectives: To determine the familial risk of syncope in first-, second-, and third-degree relatives of affected individuals and to explore the role of genes and family environment in reflex syncope. Design, Setting, and Participants: In this national population-based family cohort study, the Swedish multigeneration register was linked to 3 Swedish nationwide registers: hospital discharge, outpatient care, and primary care registers for the period from 1997 to 2015. Sibling pairs born to Swedish parents between 1948 and 2005 were included. Linkage was also made to half-siblings and cousins. Data analysis was performed from June to October 2020. Exposures: Register-based syncope diagnosis among relatives: pairs of twins, siblings, half-siblings, and cousins. Main Outcomes and Measures: Odds ratios for syncope were calculated for relatives (twins, siblings, half-siblings, and cousins) of individuals who had syncope compared with relatives of individuals without syncope for reference. Sensitivity analysis excluding families with definite nonreflex syncope diagnosis was performed. Results: Among the study population of 2 694 442 participants, 1 381 453 (51.3%) were male, and the median (interquartile range) age was 32 (22-43) years. The study population consisted of 24 020 twins, 1 546 108 siblings, 264 244 half-siblings, and 1 044 546 cousins. In total, 61 861 (2.30%) unique individuals were diagnosed with syncope. Sixty-two percent (38 226) of the syncope-positive individuals were female. The odds ratio (OR) for syncope was 2.39 (95% CI, 1.61-3.53) for twins, 1.81 (95% CI, 1.71-1.91) for siblings, 1.28 (95% CI, 1.20-1.37) for half-siblings, and 1.13 (95% CI, 1.10-1.17) for cousins of individuals with syncope. The OR was highest among male twins at 5.03 (95% CI, 2.57-9.85). The proportion of syncope-positive individuals was consistently higher in women vs men, regardless of degree of relationship (twins: 346 [2.88%] vs 193 [1.61%]; siblings: 22 111 [2.92%] vs 13 419 [1.70%], half-siblings: 4148 [3.44%] vs 2425 [1.93%], cousins: 14 498 [2.87%] vs 9246 [1.72%]). Exclusion of nonreflex syncope diagnoses did not change syncope risk in affected families. Conclusions and Relevance: In this Swedish national population-based study, the risk of syncope among relatives of affected individuals was associated with the relationship degree and was strongest in twins and siblings, which suggests that there are genetic components of reflex syncope. Women were more likely to experience syncope independently of family relationship. A better understanding of genetic predisposition to reflex syncope may offer new therapeutic options in severely affected individuals.