Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort

Abstract

Neurophysiological measurements of the response to prepulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic prepulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18 – 30 years) MA men (n=170) and women (n=250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to prepulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the prepulse/startle response in this cohort.

Endophenotype best practices

“…If a locus identified through GWAS shows different LD patterns in individuals of different ancestries, then conducting an association analysis in both ancestries can narrow the locus, thus reducing the set of credible candidate causal variants. For this reason, electrophysiological studies of different ethnic groups, such as those carried out with Native and Mexican American communities in the US (Ehlers & Gizer, 2013; Ehlers & Phillips, 2007; Ehlers, Wills, Phillips, & Havstad, 2015; Norden-Krichmar et al, 2015), are especially valuable even if they are not expected to greatly increase power to detect novel associations, nor do they obviate the need for large samples (e.g., see Table 3 ).…”