BACKGROUND: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function. MATERIALS AND METHODS: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest. RESULTS: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%). CONCLUSION: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease.

The research leading to these results has received funding from the European Research Council under the ERC Grant Agreement number 268479 – the BREATHE project. The INMA project was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041). The INMA-Sabadell cohort received funding from Instituto de Salud Carlos III (FIS-FEDER: PI041436 and PI081151), Generalitat de Catalunya-CIRIT 1999SGR 00241, and EU sixth framework project NEWGENERIS FP6-2003-Food-3-A-016320. The INMA-Valencia cohort received funding from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), and from Instituto de Salud Carlos III (FIS-FEDER: 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/0178, 11/01007, 11/02591, 11/02038, 13/1944, 13/2032, 14/00891, 14/01687 and Miguel Servet-FEDER MS15/0025) and the Conselleria de Sanitat, Generalitat Valenciana. SA is supported by a Sara Borrell grant from the Instituto de Salud Carlos III (CD14/00214). NV-T is funded by a pre-doctoral grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca (2015 FI_B00636) Generalitat de Catalunya – Fons Social Europeu. JJ is supported by a Miguel Servet (MS) Fellowship (MS14/00108) awarded by the Spanish Institute of Health Carlos III (Ministry of Economyand Competitiveness).