Since its inception the conceptual framework of molecular genetics has remained firmly grounded in the belief that genes are generally synonymous with proteins. Since the turn of the century, however, this framework has all but collapsed, following the discovery that most of the human genome is transcribed, mostly to produce long noncoding RNAs (lncRNAs), which regulate the spatiotemporal patterns of multicellular development.
Separately, genome wide association studies (GWAS) have identified haplotype blocks linked to a wide range of complex human traits, including neurodevelopmental and neuropsychiatric disorders. Most (~95%) GWAS single nucleotide polymorphisms (SNPs) reside in non-protein coding regions. High resolution transcriptomic analyses revealed most GWAS regions express lncRNAs.
We identified hundreds of brain disorder and brain complex trait-associated haplotype blocks that contain lncRNAs but lack protein-coding genes, almost all of which align to the mouse and rat genomes. Like human haplotype blocks, all mouse syntenic loci express lncRNAs, suggesting the existence of orthologs that can be manipulated to probe lncRNA-disorder/trait relationships. We present examples of lncRNAs involved in complex traits and behaviour by knocking down lncRNAs in organoids and rodents. Our analysis establishes a framework for investigating the molecular etiology of complex traits/disorders and suggests a solution to the challenge of diagnosing and treating complex disorders.