ALS in Danish Registries

Abstract

ObjectiveTo investigate the genetic contribution to amyotrophic lateral sclerosis (ALS) and the phenotypic and genetic associations between ALS and psychiatric and cardiovascular disorders (CVD) we used the national registry data from Denmark linked to first-degree relatives to estimate heritability and cross-trait parameters.MethodsALS cases and 100 sex and birth-matched controls per case from the Danish Civil Registration System were linked to their records in the Danish National Patient Registry. Cases and controls were compared for (1) risk of ALS in first-degree relatives, used to estimate heritability, (2) comorbidity with psychiatric disorders and CVD, and (3) risk of psychiatric disorders and CVD in first-degree relatives.Results5,808 ALS cases and 580,800 controls were identified. Fifteen percent of cases and controls could be linked to both parents and full siblings, whereas 70% could be linked to children. (1) We estimated the heritability of ALS to be 0.43 (95% CI, 0.34–0.53). (2) We found increased rates of diagnosis of mental disorders (risk ratio = 1.18; 95% CI, 1.09–1.29) and CVD in those later diagnosed with ALS. (3) In first-degree relatives of those with ALS, we found increased rate of schizophrenia (1.17; 95% CI, 0.96–1.42), but no evidence for increased risk CVD.ConclusionsHeritability of ALS is lower than commonly reported. There is likely a genetic relationship between ALS and schizophrenia, and a nongenetic relationship between ALS and CVD.

Cardiovascular disease, psychiatric diagnosis and sex differences in the multistep hypothesis of amyotrophic lateral sclerosis

“…As previously documented [9]; we initially identified 5808 ALS cases (3227 males and 2581 females, ratio 1.25:1), in good agreement with studies previously accessing ALS records from Danish registers [14,16,18,19]. Annual incidence was higher in later years, consistent with the previously reported increase in age‐adjusted incidence (1.6% annually after 1982 [19]) and inclusion of outpatient records from 1995.…”

“…A similar increase in ALS risk with prior cardiovascular disease (CVD) has been demonstrated by us (RR = 1.21, 95% CI: 1.15–1.27) [9] and others [13]. In contrast to the association with psychiatric illnesses, the positive association with CVD might reflect lifestyle factors rather than a genetic relationship contributing to ALS risk, because we previously found no increase in the rate of CVD among relatives of those with ALS, and genetic correlation estimates between ALS and CVD are not different from zero [9].…”

“…The Danish population registry data used for this study is described in Trabjerg et al . [9]. Briefly, it includes all persons in the Danish Civil Registration System alive in Denmark between 1 January 1968 and 1 January 2017.…”

“…Inclusion was based on persons who were living in Denmark, older than 16 years and with a diagnosis of International Classification of Diseases (ICD), Eighth Revision code 348.0 or International Classification of Diseases, Tenth Revision code G12.2. These ICD definitions have been utilized in previous Danish registry ALS studies and have good validation [9,14]. To capture incident cases only, age of diagnosis is considered age at first record in the system.…”

“…Relevant factors/steps contributing to disease onset are still to be elucidated [5,8], and those under investigation could be similarly modelled. There is evolving epidemiological [9] and genetic [10,11] evidence for an association between ALS and psychiatric illnesses, particularly schizophrenia. A significant estimate of 0.14 (95% confidence interval [CI]: 0.07–0.21) for the genetic correlation between ALS and schizophrenia has been reported [12], and our recent utilization of Danish registry data [9] found an increased risk of all psychiatric disorders (relative risk [RR] = 1.18, 95% CI: 1.09–1.29, P = 1.3 × 10 −4 ) prior to ALS diagnosis compared to age‐ and sex‐matched controls.…”