A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a familybased design. Family-and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n = 6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Autism Spectrum Disorders: Insights from Genomics

“…This is comparable with common variant discoveries in other psychiatric disorders including schizophrenia (Glessner et al, 2009) [45], bipolar disorder (Ferreira, 2008) [46], and attention-deficit/hyperactivity disorder (Arcos-Burgos et al 2010) [47]. While it is important not to undermine the significance of these findings, it should be noted that the predictive value of such ratios is relatively low [48], often explaining less than 5% of the total risk (review at http://www.genome.gov/gwastudies).…”

The Genetics of Autism Spectrum Disorders

“…For the most significant discovery SNP identified in the Wang et al study above (rs4307059), the risk allele frequency was 0.65 in cases with an odds ratio of 1.19, which is comparable with common variant discoveries in other psychiatric disorders including schizophrenia Glessner et al, 2010); bipolar disorder (Ferreira, 2008), and attention-deficit/hyperactivity disorder (Arcos-Burgos et al 2010). While it is important not to undermine the significance of these findings, it should be noted that the predictive value of such ratios is relatively low , often explaining less than 5% of the total risk (review at http://www.genome.gov/26525384).…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…The availability of low-molecular-weight substances would likely facilitate approaches to target the wide range of Adhesion GPCRs that are expressed in the brain, a tissue that cannot easily be accessed by peripherally administered antibodies owing to the presence of the blood-brain barrier. As mentioned earlier, numerous Adhesion GPCRs of clinical interest are found in the brain, with ADGRL3 (LPHN3) and ADGRB3 (BAI3) being two members of the family that have been associated with psychiatric disorders (Liu et al, 2006;DeRosse et al, 2008;Arcos-Burgos et al, 2010;Domene et al, 2011;Ribasés et al, 2011).…”

“…ADGRL3 (latrophilin-3) interacts with FLRT3, and this affects the formation and regulation of excitatory synapses (O'Sullivan et al, 2012). SNPs in ADGRL3 (LPHN3) are a risk factor for attention deficit/hyperactivity disorder (Arcos-Burgos et al, 2010;Domene et al, 2011;Ribasés et al, 2011). Loss of Adgrl3 (Lphn3) function in mice and zebrafish disturbs dopaminergic brain circuits, leading to a hyperactive/impulsive phenotype, which can be rescued by anti-attention deficit/hyperactivity disorder drugs (Lange et al, 2012;Wallis et al, 2012).…”