Study Adds to Evidence that Smoking Increases Risk for ALS

Smoking is associated with a greater risk of developing amyotrophic lateral sclerosis (ALS), according to a new study.

The research, “Smoking and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study,” appeared in the journal Annals of Neurology.

Cigarette smoking has been proposed as a risk factor for developing ALS and accelerating disease progression. However, methodological concerns hamper definitive conclusions of whether smoking causes the disease. One limitation of prior observational studies is that ALS patients may recall their smoking history differently than people without ALS, leading to recall bias. Although prospective studies could be the answer for these concerns, having unknown or unmeasured confounders could still challenge the validity of the results.

Aiming to better assess this association, the team from Karolinska Institutet, in Sweden, used so-called Mendelian randomization (MR), a method to assess whether variations in genes of known function cause a disease.

The investigators used data from the international, large-scale, whole-genome sequencing study Project MinE involving 12,577 ALS patients and 23,475 controls of European ancestry. They also used data from a genome-wide association study (GWAS) of genetic variants associated with general risk tolerance, including ever vs. never smoking, conducted by the Social Science Genetic Association Consortium with 518,633 participants of European ancestry.

The results of three different MR methods showed that those who smoked had a significantly higher risk of having ALS.

This correlation was still observed after excluding nine single nucleotide polymorphisms (SNPs) — variations in a single nucleotide, the building blocks of DNA — known for not being exclusively associated with smoking. These included breast cancer, energy expenditure, hip circumference, intelligence, reaction time, schizophrenia, psoriasis, and intraocular pressure. These nine SNPs were part of the 176 SNPs found in different loci — specific spots in chromosomes — selected as instrumental variables, a type of analysis used to control for confounding effects.

“In summary, our study provides evidence for a causal relationship between smoking and ALS,” the scientists said. Using three different MR methods developed specifically for GWAS statistics supports this conclusion, they noted.

Future studies that help understand this association could clarify the biological mechanisms through which smoking leads to ALS, the investigators said.