Abstract
Rare variants, generally referring to mutations whose frequency is less than 1%, have been targeted under the assumption that some of them should be related to psychiatric diseases. In this paper, I discuss the evolutionary nature of rare variants, deleterious variants in particular, and also explain how to assess the deleteriousness of rare variants. We searched for variants in POLG gene in Japanese patients with bipolar disorder and controls and comprehensively examined all of 23 identified variants in three different modalities of assessment : in‐silico predictions (including a recently developed, deep learning‐based program, MVP) , in‐vitro biochemical assays, and in‐vivo clinical evaluation. Every assessment achieved the same conclusion that deleterious variants were significantly enriched in patients, suggesting deleterious POLG variants as a risk for bipolar disorder. The author declare no conflict of interest.
