Genetic Variation Underpinning ADHD Risk in a Caribbean Community

Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10−4), rs2282794-FGF1 (A allele; p = 1.33 × 10−2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10−2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.

ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD

“…No children or adults were treated with medication for ADHD at initial assessment. The full neurological, neuropsychological and psychological assessment, as well as demographic information, has been reported elsewhere [49,52,53]. Briefly, 408 individuals belonging to 120 nuclear families and ascertained from probands affected by ADHD initially participated in our clinical and genetic studies of ADHD.…”

“…ADHD diagnosis was assessed in all individuals using behavioral [54][55][56] and psychopathological interviews, which include the structured Diagnostic Interview for Children and Adults (DICA) version IV [57]. This interview (1) considers the A criterion of the DSM-IV, (2) utilizes a systematic approach to collect clinical information about ADHD symptoms exhibited by an individual using a binary classification (0 = absent; 1 = present) system, and (3) has been extensively used by our group and others in genetic studies of ADHD [27,49,52,53,[58][59][60]. ADHD symptom data were collected during the clinical assessment stage, where 11 schools were visited (seven of medium socio-economic stratum).…”

“…DNA extraction and genotyping were performed as described elsewhere [52]. Briefly, genomic DNA was isolated from blood samples using the MasterPure ® DNA Purification Kit (Epicentre Biotechnologies, Chicago, IL, USA) according to the manufacturer's protocol.…”

“…We recently identified ADHD cognitive endophenotypes related to working memory and perceptual organization in nuclear families segregating ADHD [49] in a Caribbean community with one of the largest African admixtures in Colombia and South America [50][51][52]. Now, in this study, we explore whether genetic variation is a major component underpinning the biological basis of these traits.…”

Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder

“…One leading candidate gene is the BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), which has shown a consistent association with ADHD across studies 8 and meta-analytic statistical significance even after Bonferroni correction. Besides, a recent meta-analysis has highlighted another candidate gene repetitively associated with ADHD, the ADGRL3 (adhesion G protein-coupled receptor L3; formerly LPHN3 , latrophilin 3) 9 – 12 .…”