Related Experiment Video
Updated: Jan 18, 2026
08:09
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
7.9K
Genetic Modifiers of Parkinson's Disease: A Case-Control Study
Matthew J Kmiecik1, Michael V Holmes1, Pierre Fontanillas1
123andMe, Inc., Sunnyvale, California, USA.
Annals of Clinical and Translational Neurology
|September 10, 2025
Summary
Genetic factors like LRRK2 p.G2019S and GBA1 p.N409S significantly impact Parkinson's disease (PD) risk and symptoms. Polygenic risk scores (PRS) and APOE E4 also influence PD penetrance and presentation.
Area of Science:
- Genetics and Neurology
- Neurodegenerative Diseases Research
- Parkinson's Disease Etiology
Background:
- Parkinson's disease (PD) has a complex genetic basis involving specific mutations and risk alleles.
- Understanding the combined effects of genetic factors is crucial for predicting PD risk and progression.
Purpose of the Study:
- To investigate the impact of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptom profiles.
- To assess how these genetic factors interact to influence the likelihood and clinical presentation of Parkinson's disease.
Main Methods:
- A large-scale, US-based observational case-control study utilizing data from 23andMe Inc. and the Fox Insight Genetic Substudy (FIGS).
- Analysis of over 7.5 million participants, including specific cohorts of LRRK2 p.G2019S and GBA1 p.N409S carriers, dual carriers, and noncarriers.
- Utilized survival models for cumulative PD incidence and logistic regressions for symptom associations, with PRS calculated from a European genome-wide association study.
Main Results:
- By age 80, cumulative PD incidence was highest in dual LRRK2/GBA1 carriers (30%), followed by LRRK2 p.G2019S carriers (24%), GBA1 p.N409S carriers (4%), and noncarriers (2%).
- Higher PRS correlated with increased variant penetrance and earlier PD diagnosis. GBA1 p.N409S was linked to a greater non-motor symptom burden (e.g., REM sleep behavior disorder, cognitive deficits), while LRRK2 p.G2019S had the lowest.
- APOE E4 dosage increased the likelihood of reporting hallucinations and cognitive impairment.
Conclusions:
- Genetic screening can effectively identify individuals for neuroprotective trials.
- Genotype-specific outcome measures can refine clinical trial design and interpretation for Parkinson's disease.
Related Concept Videos
01:24Parkinson's Disease: Treatment
995
Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
995
01:28Human Genetics
1.5K
Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...
The complex relationship between genetics and psychology is observable through common biological components such...
1.5K
01:15Parkinson's Disease: Overview
1.8K
Neurodegenerative disorders are progressive diseases that cause irreversible damage and loss to neurons in specific brain areas. Examples of these disorders include Parkinson's disease, Alzheimer's disease, Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). These disorders share characteristics such as proteinopathies, selective neuronal vulnerability, and a complex interplay between genetic and environmental factors. The primary therapeutic goal for these conditions is...
1.8K
01:43Incomplete Dominance
29.7K
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
29.7K
01:11Genome-wide Association Studies-GWAS
15.3K
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
GWAS does not require the identification of the target gene involved in...
15.3K
01:37Neural Regulation
43.2K
Digestion begins with a cephalic phase that prepares the digestive system to receive food. When our brain processes visual or olfactory information about food, it triggers impulses in the cranial nerves innervating the salivary glands and stomach to prepare for food.
43.2K