Genetic diversity is a major factor driving phenotypic differences between individuals. The wide spectrum of heritable traits ranges from mild personality differences to extreme instances of Mendelian genetic disorders. Consequently, researchers have expended significant resources attempting to find genetic variants that contribute to phenotypic diversity, especially those relating to human disease. Past efforts have been most successful at uncovering highly penetrant mutations that occur in the protein coding regions of genes. Promoter and intronic variants can also have drastic effects on phenotype, with recent estimates suggesting that variants acting at the RNA level contribute to greater than 60% of all genetic disease. Most of these genetic variants affect RNA processing, especially transcript splicing.
Here, I present a series of studies exploring relationships between genetic variants that significantly affect RNA expression and three neurological phenotypes. First, I uncovered a transcription enhancer region contributing to nicotinic α5 receptor subunit mRNA expression and subsequently tested its relationship to nicotine addiction. Next, I revealed a significant correlation between splicing of serotonin 2A receptor mRNA transcripts and a genetic variant implicated in clinical responsiveness to atypical antipsychotics and antidepressants. Finally, in a survey of autism-related risk genes, I uncovered evidence for genetic variations affecting mRNA expression in multiple genes, including cellular adhesion molecules, alternative splicing molecules, and integral components of glutamatergic and gamma-aminobutyric acid signaling. The broad range of neurological phenotypes affected by non-protein coding variants investigated here suggests a pervasive role for RNA processing in human disease. The accumulation of these RNA processing variants throughout human evolution is discussed in the context of human disease.