<p id="P3">To identify novel genes associated with ALS, we undertook two lines of
investigation. We carried out a genome-wide association study comparing 20,806
ALS cases and 59,804 controls. Independently, we performed a rare variant burden
analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through
both approaches, we identified
<i>kinesin family member 5A (KIF5A)</i>
as a novel gene associated with ALS. Interestingly, mutations predominantly in
the N-terminal motor domain of KIF5A are causative for two neurodegenerative
diseases, hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth Type 2
(CMT2). In contrast, ALS associated mutations are primarily located at the
C-terminal cargo-binding tail domain and patients harboring loss of function
mutations displayed an extended survival relative to typical ALS cases. Taken
together, these results broaden the phenotype spectrum resulting from mutations
in
<i>KIF5A</i> and strengthen the role of cytoskeletal defects in the
pathogenesis of ALS.
</p><p id="P4">Using large-scale genome-wide association study and exome sequencing,
we
identified
<i>KIF5A</i> as a novel gene associated with ALS. Our data
broaden the phenotype resulting from mutations in
<i>KIF5A</i> and
highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
</p>