Frontotemporal lobar degeneration association study using sequence data

We hypothesize that patients with AD and FTD share common genetic factors. We generated whole-genome sequencing data from over 500 FTD patients and 800 controls and identified new genetic variants associated with FTD. Our findings add to the growing body of genetic factors associated with both diseases (TREM2, MAPT, GRN, and C9ORF72). We have now extended our cohort of whole-genome sequenced FTD and controls. We are requesting access to the ADSP whole-genome sequencing data (raw and VCF) to i) use the ADSP controls in order to increase our statistical power to detect risk variants in FTD by increasing the size of our control set, and ii) to perform gene-based, single variant and pathway association analyses in ADSP data with candidate FTD/ALS genes to determine their impact across dementias. Single nucleotide variants, as well as structural variants, will be assessed.
To do so, we will call variants combining our FTD data with ADSP data starting from the raw files and using the same pipeline as the one already used for our FTD genome data. ADSP raw files will be processed through the Mayo Clinic Genome-GPS (GGPS) analytic pipeline and the ANNOVAR variant annotation pipeline. In addition, we will also run the ADSP’s data with specific pipelines more accurate for complex genomic regions such as the HLA risk region, e.g. HISAT2. We will also use new genotyping technologies such as long-read sequencing to impute structural variants in the ADSP dataset and compare them to our findings in our FTD cohort.
We will utilize several commonly used software programs, such as Plink-seq and SKAT package, to perform our association analyses. Control data will be used to perform a large association study on FTD patients and controls. Then, association studies within the ADSP dataset will be performed. All analyses will be done at the single variant, gene, structural variant, and pathway levels.
Using these approaches, we hope to identify novel mutations/genes/pathways that are related to both AD and FTD and will benefit the larger scientific community working on neurodegenerative disorders.

Frontotemporal dementia (FTD) is the second most common form of early-onset dementia after Alzheimer’s disease (AD). While AD patients initially present with memory problems, FTD patients usually present with changes in personality and behavior and sometimes language problems. However, clinical and genetic overlaps between both diseases have been reported.
We propose to perform in-depth genetic studies to identify genetic factors that cause or increase the risk for FTD and comprehensively assess the genetic overlap between AD and FTD. The identification of new disease genes will provide novel insight into the disease biology; may improve genetic counseling in patients, and could provide new targets for future therapeutic interventions.