Berkeley Lab researchers study mice to shed light on genetic risks of Alzheimer’s and other diseases
Many neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease, share common symptoms such as impaired motor function. Increasing evidence also points to connections between body weight—particularly obesity in midlife—and the risk or timing of neurological disease onset. However, the genetic factors that link motor impairment, obesity, and neurodegenerative disease remain poorly understood. Clarifying these links could reveal underlying causes and suggest new avenues for treatment.
Researchers at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have advanced that effort by identifying genetic regions that influence motor performance and body weight in a genetically diverse mouse population. Their study shows significant overlap between the mouse genes they identified and human genes previously associated with neurological disorders and obesity.
Published in Scientific Reports on November 9, the work provides further evidence that obesity and neurodegenerative disease are genetically connected and offers a practical framework to guide future human studies of the genetic roots of neurological conditions.
“This study establishes a framework for exploring genetic links between motor skills, body weight, and central nervous system disorders,” says Antoine Snijders of Berkeley Lab’s Biological Systems and Engineering Division, who led the research with Jian-Hua Mao and other colleagues.
The team used the Collaborative Cross (CC), a newly developed panel of laboratory mouse strains designed to capture the broad genetic diversity seen in humans. The CC model represents nearly 90 percent of genetic variation among lab mice and includes many genes that are conserved between mice and humans. Because about 95 percent of human disease genes are present in the mouse genome, the CC provides a powerful platform to dissect genetic contributions to complex traits while controlling environmental variables such as diet and housing.
Using 365 mice from 16 Collaborative Cross strains, the researchers measured body weight and performance on the rotarod test at ten weeks of age. The rotarod is a rotating rod that gradually increases in speed, challenging a mouse’s balance and coordination. As expected for a genetically diverse cohort, rotarod performance and body weight varied widely across strains, and heavier mice generally performed worse—falling off sooner—than lighter mice.
Genetic linkage analysis revealed that both traits are highly polygenic. The researchers mapped 14 genomic regions associated with body weight and 45 regions associated with rotarod performance. Seven regions were shared between the two traits, yielding a total of 52 distinct genomic intervals linked to motor ability and body mass.
To assess relevance for human health, the team compared the 1,694 mouse genes located in the 52 regions with human genes implicated in obesity and neurological disorders through genome-wide association studies (GWAS). They identified 103 mouse genes in 39 of the mapped regions that overlap with 1,766 human genes tied to these conditions.
For example, of the 186 human genes highlighted by GWAS as associated with Alzheimer’s disease, seven were located within the mouse genomic intervals identified in this study. Similarly, of roughly 834 genes implicated in human obesity, 48 overlapped with genes found to influence rotarod performance or body weight in the mice. The analysis also showed meaningful overlaps with genes associated with Parkinson’s disease, multiple sclerosis, and other neurological conditions.
“These results show that the Collaborative Cross mouse resource is a valuable tool for pinpointing genetic risk factors that may underlie neurological disorders and metabolic traits,” says Jian-Hua Mao.
Beyond motor performance and weight, Mao and Snijders are applying the Collaborative Cross mice in Berkeley Lab’s Microbes to Biomes project to investigate interactions among gut microbes, host genetics, and environmental influences—another frontier in understanding disease risk and resilience.
Funding: This research was supported by Berkeley Lab’s Microbes to Biomes Laboratory Directed Research and Development program and by the Office of Naval Research.
Source: Dan Krotz – Berkeley Lab
Image Source: The image is in the public domain
Original Research: Full open access research: “Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice” by Jian-Hua Mao, Sasha A. Langley, Yurong Huang, Michael Hang, Kristofer E. Bouchard, Susan E. Celniker, James B. Brown, Janet K. Jansson, Gary H. Karpen and Antoine M. Snijders in Scientific Reports. Published online November 9, 2015. DOI: 10.1038/srep16247
Abstract
Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice
Emerging evidence links motor deficits, obesity, and many neurological disorders, but the genetic contributors remain unclear. Using the Collaborative Cross, a diverse panel capturing most known laboratory mouse variation, we analyzed rotarod performance and body weight in 365 mice across 16 CC strains. Both traits varied widely and were significantly negatively correlated. Genetic linkage analysis mapped 14 loci associated with body weight and 45 loci affecting rotarod performance; seven loci influenced both traits, indicating a genetic connection. Genes identified in these intervals show significant overlap with human GWAS results for neurological diseases and obesity. These findings provide a genetic framework to study interactions among body weight, the central nervous system, and behavior.
“Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice” by Jian-Hua Mao et al., Scientific Reports. Published online November 9, 2015. DOI: 10.1038/srep16247