Objectives: Startle response is an objective physiological measure integral to the human defense system and a promising target for endophenotype investigations of anxiety. Given the alterations in startle reactivity observed among anxiety and related disorders, we searched for genetic variants associated with startle reactivity as they may be further involved in pathological anxiety risk.
Methods: A systematic literature review was performed to identify genetic variants associated with startle reactivity in humans, specifically baseline and fear- or anxiety-potentiated startle.
Results: The polymorphisms Val66Met (rs6265) from brain-derived neurotrophic factor (BDNF), Val158Met (rs4680) from catechol-O-methyltransferase (COMT), and the serotonin transporter-linked polymorphic region (5-HTTLPR) from the serotonin transporter gene (SLC6A4) were most commonly studied in human startle. In addition, several other genetic variants have also been identified as potential candidates that warrant further research, especially given their novelty in in the context of anxiety.
Conclusions: Similar to psychiatric genetic studies, the studies on startle reactivity primarily focus on candidate genes and are plagued by non-replication. Startle reactivity is a promising endophenotype that requires concerted efforts to collect uniformly assessed, large, well-powered samples and hypothesis-free genome-wide strategies. To further support startle as an endophenotype for anxiety, this review suggests advanced genetic strategies for startle research.
Keywords: Startle; anxiety; endophenotype; genetics; single nucleotide polymorphism.