Influence of a latrophilin 3 (LPHN3) risk haplotype on event-related potential measures of cognitive response control in attention-deficit hyperactivity disorder (ADHD)

Abstract

Current research strategies have made great efforts to further elucidate the complex genetic architecture of attention-deficit hyperactivity disorder (ADHD). The present study examined the impact of an LPHN3 haplotype that has recently been associated with ADHD (Arcos-Burgos et al., 2010) on neural activity in a visual Go-NoGo task. Two hundred sixteen adult ADHD patients completed a Continuous Performance Test (CPT) while the ongoing EEG was simultaneously recorded. Results showed that patients carrying two copies of the LPHN3 risk haplotype (n=114) made more omission errors and had a more anterior Go-centroid of the P300 than patients carrying at least one LPHN3 non-risk haplotype (n=102). Accordingly, the NoGo-Anteriorization (NGA; topographical ERP difference of the Go- and NoGo-condition), a neurophysiological marker of prefrontal functioning, was reduced in the LPHN3 high risk group. However, in the NoGo-condition itself no marked differences attributable to the LPHN3 haplotype could be found. Our findings indicate that, within a sample of ADHD patients, the LPHN3 gene impacts behavioral and neurophysiological measures of cognitive response control. The results of our study further strengthen the concept of an LPHN3 risk haplotype for ADHD and support the usefulness of the endophenotype approach in psychiatric and psychological research.

Figure 1

Grand average curves for the CPT Go (blue; Pz) and NoGo condition (red; Cz) in patients with no copy (n=17) or one copy (n=85) of the LPHN3 risk haplotype (low risk group; A) vs. patients homozygous for the risk haplotype (n=114; high risk group; B). Maps above the curves display the brain electrical field at the time-point of the P300 peak at Pz (Go condition; left map of a pair) and Cz (NoGo condition; right map of a pair), respectively. The difference map for the comparison of the two haplotype groups with respect to the Go-centroid (high minus low risk group) is depicted in the left part of the figure (C). Right panel depicts the main result of a reduced NoGo-Anteriorization in LPHN3 high risk carriers (vertical bars represent the standard error of the mean) (D). (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 2

Source localization of the difference in P300 data between genotype groups for the Go conditions of the CPT; sLORETA image displays the maximum difference, which was found in Brodman Area 10 (middle frontal gyrus) where patients of the LPHN3 low risk group (n=102) tended to exhibited stronger activation values than patients of the high risk group (n=114; p=0.1).

Figure 3

Analysis of potential gene-dose effects for omission errors (left panel) and the NGA (right panel).