There have been some early success stories from sequencing of candidate genes for common diseases and traits, e.g. IFIH1 rare alleles provide some protection from type 1 diabetes (73) and sequencing candidate genes LDLR and PCSK9 (12) has identified rare variants associated with high and low LDL levels, respectively. Despite much debate and statistical modeling, it is currently unknown how substantial a role rare variants will play in common diseases. Large-scale sequencing studies in tens of thousands of individuals may be needed to resolve this debate and meta-analysis or mega-analysis of data from many investigators may be essential, as discussed below.
