A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

Genetics studies have revealed a genetic contribution to susceptibility for common or sporadic forms of neurodegenerative disease such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supra-nuclear palsy (PSP, a syndrome characterized by oculomotor and gait abnormalities). In AD, early genetic mapping approaches have identified rare variants in genes such as APP, PSEN1, and PSEN2that cause familial, early-onset forms.1 APOE was also pinpointed as a late-onset AD susceptibility gene.2 Genome-wide association studies3–5 (GWAS) targeted toward common variants in primarily European populations have identified many variants associated with AD, most clearly near APOE but also consistently near ABCA7, BIN1, CLU, CR1, PICALM, SORL1, and other genes. Next-generation sequencing approaches have also found rare variants with strong effect in the MAPT and TREM2 genes.6,7 In FTD, the most frequently observed mutations in familial cases occur in C9ORF72, GRN, MAPT, TARDBP, and other genes.8 In sporadic cases, a haplotype variant on the long arm of chromosome 17 has been repeatedly associated with PSP.9–11 In addition, GWAS have been performed for sporadic cases of FTD, identifying associated single-nucleotide polymorphisms (SNPs) near TMEM106B12 and BTNL2/HLA-DRA/HLA-DRB5 and RAB38/CTSC,13 as well as for PSP, identifying associated SNPs near MAPT, EIF2AK3, STX6, and MOBP.11 Despite progress in understanding the genetics of neurodegenerative diseases, known genetic risk factors cannot explain a large portion of the heritability of these diseases. For example, in AD, all common variants (including known and unknown risk variants) have been predicted to account for less than 25% of disease variance,14 and known high-penetrance rare variants account for few cases, collectively totaling only a fraction of the estimated 58% to 79% heritability of AD.15 Some of this missing heritability may be due to a blind spot in conventional genetic studies to date. A moderately rare variant with moderate effect size would be too uncommon to be tagged by a standard genotyping array and have too small of an effect to be detected by linkage or genome sequencing in practical sample sizes. The exome array bridges this gap by genotyping at low cost more than 200 000 coding variants identified through sequencing studies (Figure 1). This approach has been applied to phenotypes such as insulin homeostasis,16 bronchopulmonary dysplasia,17 and heart disease.18,19 For AD, Chung et al20 recently reported an exome array study in Korean participants that found an association with APOE, APOC1, and TOMM40 variants (near the APOE locus) but did not identify novel genetic variants. Herein, we report findings from the application of the exome array to the multiancestral Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study cohort to determine the contribution of low-frequency coding variants to susceptibility to sporadic AD, PSP, and FTD. Figure 1 Comparison of the Exome Array and Related Genotyping and Sequencing Technologies