Study in Twins Links Age-Related Changes in DNA Methylation with ALS

A study in identical twins or triplets found that changes in DNA marks, collectively known as DNA methylation and typically associated with aging, can like genetics play an important role to determining the development of amyotrophic lateral sclerosis (ALS).

The four sets of ALS-affected and unaffected siblings carried age-related differences in methylation patterns across the genome (the complete set of genes or genetic material present in an organism), the researchers report. They also identified genes that may explain why some people are more susceptible or more resistant to the disease, and may help identify targets for possible treatment.

The findings were described in the study “Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression,” published in the journal Scientific Reports.

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is a progressive neurological disease that causes gradual destruction of motor neurons, which control voluntary muscle movement.

ALS has variable manifestations, including age, site of onset, and disease duration, but two common forms: sporadic ALS, which accounts for about 90 percent of ALS cases marked by the disease’s cause not being well-understood; and familial ALS, caused by mutations at certain genes inherited from a parent.

Some studies suggest that beyond mutations, other kinds of genetic changes can influence a person’s susceptibility to ALS.

Research looking at the whole methylome (the entire set of DNA methylation marks across the genome), and transcriptome (gene readouts across the whole genome) in spinal cord tissue and blood have found global changes. That work implicated various genes and biological pathways, including immune responses and transport within cells.

DNA methylation refers to the attachment of a chemical group (methyl group) to DNA. This type of DNA modification is called epigenetic, which means it does not change the DNA sequence itself but can affect gene activity. For instance, the presence of a methyl mark can turn a gene “off” and stop it from driving the production of a protein.

Researchers here compared the methylome and transcriptome of identical (monozygotic) twins and triplets — some of whom developed ALS while others had not.

Identical twins share the same genome; that is, they have the same DNA sequence for all genes. For many years scientists have been studying twins to find out which genetic mechanisms beyond inherited genes — such as DNA methylation and gene activity — contribute to human traits and disease.

The four pairs studied represented both sporadic ALS (one pair of male and one of females twins) and twins with most common types of familial ALS, linked to C9orf72 (one twin pair) and to SOD1 (one triplet) mutations. In each pair of twins or triplets, only one individual had ALS.

Researchers analyzed methylome and transcriptome data, independently and in combination, in an attempt to identify disease-relevant changes and their potential impact on the disease.

Results showed a significant interaction between age, disease status and methylation, with older twins showing consistent differences in DNA methylation between ALS-affected and unaffected co-twins.

Age-associated changes in DNA methylation, also known as DNA methylation age, are well-documented and thought to promote such diseases of aging as cancer. Recent studies also have identified groups of individual methylation sites across our genome, which trace with chronological age and are referred to as the DNA methylation clock.

Data now gathered suggest this pattern, DNA methylation age, is also an important factor contributing to ALS.

By comparing gene activity and DNA methylation changes across all twin and triplet sets, the researchers also identified several genes likely to influence ALS, either by contributing to or protection from disease. “These genes and pathways offer potential targets for future therapeutic treatment for ALS,” they wrote.

The findings suggest that people with ALS appear to carry changes in gene activity (transcriptome changes) and DNA chemical marks (epigenetic changes) important for determining disease that may be highly complex and affect different pathways, and only some of which are shared among patients.