Broce, I. | Search bioRxiv

bioRxiv2018

Lipid associated polygenic enrichment in Alzheimer’s disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimers disease (AD) pathogenesis. Beyond the [isin]4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimers risk.

genetics↗

bioRxiv2017

Laterality of the frontal aslant tract (FAT) explains externalizing behaviors through its association with executive function.

We investigated the development of a recently-identified white matter pathway, the frontal aslant tract (FAT) and its association to executive function and externalizing behaviors in a sample of 129 neurotypical children ranging in age from 7 months to 19-years. We found that the FAT could be tracked in 92% of those children, and that the pathway showed age-related differences into adulthood. The change in white matter microstructure was very rapid until about 6-years, and then plateaued, only to show age-related increases again after the age of 11-years. In a subset of those children (5-18-years; n = 70), left laterality of the microstructural properties of the FAT was associated with greater attention problems as measured by the Child Behavior Checklist (CBCL). However, this relationship was fully mediated by higher executive dysfunction as measured by the Behavior Rating Inventory of Executive Function (BRIEF). This relationship was specific to the FAT--we found no relationship between laterality of the white matter of the brain in general and attention problems, or executive function. These findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.\n\nSignificance StatementTo investigate the function of a recently-identified white matter fiber pathway, the frontal aslant tract (FAT), we tracked the pathway in 129 typically developing children using diffusion-weighted magnetic resonance imaging (DW-MRI). We then examined whether laterality of the tract is associated with attention problems and executive function. We found that reduced right laterality of the tract was associated with greater executive dysfunction, which predicted increased reports of attention problems. The findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.

neuroscience↗