We observed an about 10-fold risk of ALS among the singleton full siblings and children of ALS patients, with a higher relative risk among the siblings. A few studies have assessed the association between a family history of ALS and the risk of ALS 4-6
, with one study showing an around three-fold 5
and another more than 10-fold 4
risk among families of ALS patients. The various findings are likely due to different study designs and small sample sizes in these studies. Similar to our study, the only twin study available to date found 2 out of 26 monozygotic, but none out of 51 dizygotic, twin pairs with concordant ALS.10
Contrary to the siblings and children, no statistically significant excess risk of ALS was noted among the spouses of ALS patients in our study. Spouses identified via a common child might not in fact live together with the proband, thus could possibly lead to an underestimated relative risk if the shared adulthood environment does matter. Alternatively, genetic factors could clearly contribute to the different relative risks found between the blood relatives and the spouses. Other non-genetic factors specifically shared by the blood relatives, but not spouses, and the probands may have also contributed to the elevated risk. Retroviral infection, for instance, may be a potential candidate. A recent study showed that ALS cases and their blood relatives had similar loads of serum reverse transcriptase activity (an enzyme characterizing retroviral infections), while the loads were lower in spouses, who had levels similar to that of the unrelated controls.11
Although the absolute risks of ALS in siblings and children of ALS probands increased with age (), as were true in the general population, the relative risks of ALS decreased with both increasing age of ALS diagnosis of the probands () and increasing attained age of the relatives (). The result is consistent with findings from other neurodegenerative disorders such as Alzheimer's disease, where the relative risk peaked among the younger relatives of younger probands and dropped sharply both as the age at onset of the proband and the attained age of the relative increased 12
and Parkinson's disease, where the relative risk among relatives of early-onset probands was 4.7, while among relatives of late-onset probands 2.7. 13
The siblings appeared to have a higher relative risk compared to the children of ALS patients. The difference persisted after multiple adjustments for attained age at follow-up, sex, and calendar period. One possible explanation is that siblings are on average older than children and thus more likely to develop an age-dependent disease like ALS. In our study, the mean age at the end of follow-up between siblings and children differed by seven years. Separate analyses for siblings and children showing higher relative risks for the siblings in most age groups allayed such a concern. Given that siblings and children share the same number of genes with the probands, other explanations should be sought. One candidate explanation is recessive gene action. Siblings have the same chance as the proband case to inherit both recessive alleles from their common parents and develop the phenotype, while children inherit only one allele from the proband parent and their phenotypes thus depend on the other parent. Another potential explanation is the same early life exposures shared by the proband and their siblings but not their children, such as childhood infections which may modify the risk of ALS later in life.
We have no clear explanation for the relative risk difference on having a maternal versus a paternal proband, noted in our study. It is possible that, in some cases, the father reported in the registry was not the biological father of the child. Hypotheses concerning mitochondrial inheritance, parent-of-origin, and epigenetic phenomenon could be of value for further investigation. Preferential maternal inheritance through mitochondrial DNA has been suggested playing a role in familial ALS with yet conclusive evidence.14,15
Parent-of-origin effect operating through the maternal lineage, as proposed for multiple sclerosis,16
may also be possible.
Our study had potential limitations. First, we had around 40% missing data in the Multi-Generation Register for individuals deceased between 1968 and 1990. If some deceased ALS cases belong to this missing, their corresponding relatives would be classified as part of the reference group, leading to an elevated baseline risk and an underestimated relative risk. Second, we could only identify ALS cases from the registers and may have lost some cases neither hospitalized nor deceased. Death certificate is shown able to identify 70-90% of ALS cases 17
and in our data, for example, 77% of cases first hospitalized in 1991 were also found in the Causes of Death Register. We thus believe that these two registers should have captured the vast majority of ALS cases in Sweden. Given the big sample size, we were not able to verify the accuracy of ALS diagnosis. However, our sensitivity analyses by excluding death-certificate only cases or including deaths with ALS as a contributory cause showed largely unchanged results. The third limitation is that register-based data had no information on other features of interest including site of disease onset, thus preventing evaluation of relative risk variation associated with these features.
Genetic factors may play a role in the so-called sporadic cases. The discovery of mutations in SOD1
in 2-7% of sporadic cases 18-21
supports this notion. Unfortunately, we had no information on prior familial history of ALS for probands in our study. Under some assumptions, we can, however, roughly estimate the genetic effects on sporadic ALS cases. If we assume that number and age distribution of first degree relatives did not differ between familial and sporadic probands, the accumulated person-time can be partitioned into two parts, 10% for familial and 90% for sporadic probands, given that around 10% cases are familial. By multiplying the age-specific incidence rates of the reference group to the observed person-time, as well as an assumed “real” relative risk for familial ALS (contrary to the observed relative risk in our study), the expected number of ALS cases in relatives of familial probands could be calculated (termed “A”). Similarly, the expected number of cases among relatives of sporadic probands, assuming no genetic effects, can also be estimated (termed “B”). The role of genetic component in the 90% sporadic cases could thus be assessed as a ratio (((observed ALS cases) - A)/B). We observed 46 cases among the siblings and children, thus, by assuming a “real” relative risk for familial ALS as 75 (half the value of monozygotic co-twins), the ratio was 3.9 for siblings and children of sporadic probands.
Finally, we observed only two monozygotic twin pairs with concurrent ALS and could not compare the relative risks between monozygotic and dizygotic co-twins of ALS patients. But the fact that the relative risk among all co-twins of ALS probands was double that of the singleton siblings together with the even more striking relative risk among the monozygotic co-twins strongly suggests a significant role of genetics in ALS etiology. Studies able to pool twin registers from different countries are preferably warranted.
Despite limitations discussed above, our study has several significant strengths. First is the prospective cohort design, population-based approach, large sample size, and the close to complete and long-term follow-up. Second is the unbiased identification of familial history of ALS through computerized nationwide registers, which minimized the possibility of exposure misclassification. And finally, we were able to compare the relative risks of ALS between blood relative and spouses, between siblings and children, and between co-twins and singleton full siblings, of ALS patients. These strengths ensured both the validity and uniqueness of our study.
In conclusion, we observed an almost 10-fold increase in ALS risk among the siblings and children, but not spouses, of ALS patients in Sweden. The excess risk appeared higher among the siblings compared to the children, and probably also among those with a maternal proband compared to those with a paternal proband. The excess risks were most notable when the proband patients were diagnosed at a younger age, indicating a major genetic role in familial ALS, particularly for early-onset ones. Future studies in different populations are warranted to confirm our observations.