G2019S mutation carriers in LRRK2 gene have higher Parkinson’s risk

Noncarriers developed disease later, had more nonmotor symptoms

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A fraying rope illustrates increasing risk.

People who carry the G2019S mutation in the LRRK2 gene, the most common one associated with Parkinson’s disease, have a 10 times higher risk of developing the disease, but the risk increases to 27 times if mutations in other genes are also present.

G2019S carriers developed the disease earlier, but, despite the higher risk, had fewer nonmotor symptoms than noncarriers, including cognitive and olfactory deficits.

That’s according to findings from the world’s largest study on LRRK2 G2019S, which was conducted by scientists at 23andMe with the support of the Michael J. Fox Foundation.

“This suggests that the current prodromal [early] criteria, which are based on idiopathic [of unknown cause] PD [Parkinson’s disease], may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers,” the researchers wrote in “Genetic analysis and natural history of Parkinson’s disease due to the LRRK2 G2019S variant,” which was published in Brain. The results, “may have implications for the design of early interventional trials in LRRK2 G2019S carriers, including the need for more precise prodromal clinical criteria to detect early disease onset,” they said.

In Parkinson’s, there is a progressive loss of dopaminergic neurons, the nerve cells that make the chemical messenger dopamine, which most often occurs in people with no known genetic or family ties to the disease.

In about 10% of cases, however, the disease is caused by inheriting certain mutations, the most common occurring in the LRRK2 gene. Of those, 5% have a specific mutation in LRRK2 called G2019S, which is thought to keep LRRK2, an enzyme important for cellular metabolism, in an active form longer, letting it run amok inside cells.

To better understand how the mutation affects disease manifestation and whether patients’ clinical course differs from those without the mutation, scientists analyzed data from 23andMe’s Parkinson’s Impact Project (PIP), which was launched in 2018 to know more about LRRK2 G2019S carriers. Adults in the U.S. who tested positive for the mutation were invited to participate in a 3.5-year follow-up study, along with noncarriers, or people without the mutation, who served as controls.

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Comparing G2019S mutation carriers, noncarriers

The analysis included 1,286 LRRK2 G2019S carriers and 109,154 noncarriers. The participants responded to an online survey every six months. About two-thirds (66%) completed at least one follow-up. At the start of the study, 188 LRRK2 G2019S carriers and 2,113 noncarriers had been diagnosed with Parkinson’s. A total of 42% of those with Parkinson’s had at least two years of follow-up.

LRRK2 G2019S carriers were more likely to be women and have a first-degree relative with Parkinson’s. The risk of developing Parkinson’s was 10 times higher in carriers than noncarriers and grew to 27 times in the top 25% of LRRK2 G2019S carriers with other genetic variants linked to the disease. LRRK2 G2019S carriers were also diagnosed with Parkinson’s earlier than noncarriers.

Among those who developed Parkinson’s, G2019S mutation carriers had milder symptoms and the mutation was associated with a slower disease progression. Carriers had significantly fewer nonmotor symptoms, but no differences were seen between carriers and noncarriers regarding motor symptoms, suggesting brain regions not linked with motor control are somewhat protected from the neurodegenerative process in LRRK2 G2019S carriers.

Compared with noncarriers, LRRK2 G2019S patients reported lower rates of cognitive decline (8% vs. 3%), decreased sense of smell (49% vs. 32%), REM sleep behavior disorder (RBD, 23% vs. 9%), and memory deficits. RBD and a poor sense of smell can be early signs of neurodegeneration, appearing decades before typical motor symptoms such as tremors and imbalance become visible.

“Because people with the LRRK2 G2019S variant are less likely to have sleep and smell abnormalities, the scientific and medical communities might be underestimating the risk of Parkinson’s disease in LRRK2 carriers,” Lucy Norcliffe-Kaufmann, PhD, the study’s lead scientist at 23andMe, said in a press release. “Existing criteria may lack sensitivity for early detection among LRRK2 carriers. If we are only looking for smell and sleep problems, which don’t appear as often in the early stages of LRRK2-PD, we may be miscalculating a person’s risk, because for some reason those areas of the brain are more resistant to neurodegeneration.”

An ancestry analysis showed the LRRK2 G2019S mutation originated in North Africa and was passed through the early Jewish settlers there. North African and Ashkenazi Jewish populations are known to carry high rates of the LRRK2 mutations.

The findings, however, revealed a much higher rate than expected of LRRK2 G2019S carriers in Mexico, Cuba, Puerto Rico, and Brazil. This is consistent with historical records when Jews migrated to the American continents, particularly during the late 15th century.

“By understanding the genetic ancestry of LRRK2 carriers, we can build community among these people,” Norcliffe-Kaufmann said.