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    236—Brain Wellness

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    236.05: Obesity gene NEGR1 is associated with white matter integrity differently in young and old adults

    Location: Halls B-H

    1Lab. of Neuroimaging, UCLA, Los Angeles, CA; 2Ctr. for Advanced Imaging, 3Sch. of Psychology, Univ. of Queensland, Brisbane, Australia; 4Queensland Inst. of Med. Res., Brisbane, Australia

    Abstract Body: Obesity is a major public health issue in the developed world. Obesity is associated with many health issues, and high body mass index (BMI) in midlife has been linked to decreased cognitive functioning in old age. Several studies report abnormalities in white matter volume or diffusivity associated with obesity. This is likely due in part to genes that affect both the brain and obesity risk. We investigated whether common variants in obesity-associated genes might also be associated with brain measures.
    We scanned 409 subjects (264 females/145 males, mean age=23.8, range=20-29 years) at 4T with 105-gradient HARDI (high angular resolution diffusion imaging) and T1-weighted MRI. We began with a multi-locus approach that models the combined effect of a number of SNPs (single nucleotide polymorphisms) associated with obesity. This is a novel approach to examine the aggregate influence of genetic variants. We then performed a voxel-wise fractional anisotropy (FA) analysis on the SNP that appeared to be driving the association. We controlled for age, sex, BMI, and kinship (in our twin sample). The sample was split in half to test reproducibility of these results. Additionally, we attempted to replicate our results in an older group from the ADNI2 cohort (78 subjects, 29 females/49 males, mean age 74.3, range=55-90).
    In our initial multi-locus analysis, our BMI SNP panel was significantly associated with FA in the bilateral posterior corona radiata. The SNP appeared to be driving the association was in NEGR1 (rs2815752). A follow-up analysis yielded lower FA with risk allele dosage across extensive areas of white matter (see Figure 1). This association was robust in our split-sample replication. In the ADNI2 cohort, the same areas were associated with NEGR1 risk allele dosage, but in the opposite direction. Previous research has found that midlife obesity can be cognitively detrimental, while late-life obesity can be cognitively protective. Our results mirror this trajectory, and may be part of the mechanism underlying it.

    Lay Language Summary: Our research is the first to show an association between the obesity risk gene NEGR1 and brain imaging measures. We found that young individuals carrying the risk variant of NEGR1 had lower white matter integrity. An analysis of older individuals showed an opposite association, however.
    Obesity is currently one of the most pressing public health issues facing the United States and other developed countries. Obesity has long been known to be associated with health issues such as diabetes, heart disease, and even premature death, but more recently obesity has also been linked with an increased risk of developing dementia. The most immediate causes of obesity are diet and lifestyle, but we also know that a number of genes are also involved. In our study we examined how genes associated with obesity risk might also be linked with differences in the brain. We found a gene that has a detrimental effect on the integrity of the white matter in the brains of young adults, but has the opposite effect in elderly individuals.
    To examine the effects of obesity-risk genes on white matter integrity, we first ran an analysis that examined how a panel of gene variants associated with BMI (body mass index) converged in their associations with brain maps. Our initial sample included 499 subjects between 20-30 years old. These results focused our attention on one gene, NEGR1. We followed-up this initial analysis by analyzing an older group of individuals: 78 subjects between 55-90 years old. Ours is the first paper to show an association between the obesity risk gene NEGR1 and brain imaging measures.
    Our initial analysis led us to the gene NEGR1, which was driving the associations between brain structure and our panel of genetic variants related to obesity. NEGR1 was associated with decreased white matter integrity across a wide area of the brain. These effects were not due to subjects being overweight, and the subjects were young so it is less likely that our results were due to lifestyle. When we analyzed the older subjects, we found associations in the same areas as the young subjects, but in the opposite direction. This sounds odd, but the same studies that found that a high BMI in mid-life increases dementia risk later also found that a high BMI in old age was actually protective against dementia.
    The association between BMI and dementia risk is age-dependent, as is our association between NEGR1 and white matter integrity. There are many studies linking dementia to compromised white matter integrity, so these effects could be related. Future work should examine how NEGR1 is associated with white matter integrity in other age ranges.