Frequent functional orthology of long noncoding RNAs and genomic loci associated with complex traits and disorders

Genome wide association studies (GWAS) have identified many haplotype blocks linked to a wide range of complex human traits, including intelligence, neuropsychiatric disorders, and immunological disorders, among many others. Approximately a quarter of these haplotype blocks lack protein-coding sequences but most express long noncoding RNAs (lncRNAs). Here we show that human loci orthologous with mammalian lncRNAs involved in neurological or immunological functions are commonly associated with a human trait that is commensurate with the reported lncRNA function. We also show that for many neurological, autoimmune, and cancer complex traits, the vast majority (>90%) of associated haplotype blocks express one or more lncRNAs. We present a database of lncRNAs expressed from human haplotype blocks associated with GWAS traits, with their mouse orthologs, as a resource for functional analysis. Our analyses establish a framework for investigating the molecular etiology of complex traits and suggest a general solution to the challenge of diagnosing and treating complex disorders.