Analysis of shared homozygosity regions in Saudi siblings with attention deficit hyperactivity disorder

Abstract

AimGenetic and clinical complexities are common features of most psychiatric illnesses that pose a major obstacle in risk-gene identification. Attention deficit hyperactivity disorder (ADHD) is the most prevalent child-onset psychiatric illness, with high heritability. Over the past decade, numerous genetic studies utilizing various approaches, such as genome-wide association, candidate-gene association, and linkage analysis, have identified a multitude of candidate loci/genes. However, such studies have yielded diverse findings that are rarely reproduced, indicating that other genetic determinants have not been discovered yet. In this study, we carried out sib-pair analysis on seven multiplex families with ADHD from Saudi Arabia. We aimed to identify the candidate chromosomal regions and genes linked to the disease.Patients and methodsA total of 41 individuals from multiplex families were analyzed for shared regions of homozygosity. Genes within these regions were prioritized according to their potential relevance to ADHD.ResultsWe identified multiple genomic regions spanning different chromosomes to be shared among affected members of each family; these included chromosomes 3, 5, 6, 7, 8, 9, 10, 13, 17, and 18. We also found specific regions on chromosomes 8 and 17 to be shared between affected individuals from more than one family. Among the genes present in the regions reported here were involved in neurotransmission (GRM3, SIGMAR1, CHAT, and SLC18A3) and members of the HLA gene family (HLA-A, HLA-DPA1, and MICC).ConclusionThe candidate regions identified in this study highlight the genetic diversity of ADHD. Upon further investigation, these loci may reveal candidate genes that enclose variants associated with ADHD. Although most ADHD studies were conducted in other populations, our study provides insight from an understudied, ethnically interesting population.

Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

“…Our findings from both studies (here and [36]) are in keeping with the notion that ADHD does not conform to a monogenic model. Moreover, while homozygosity analysis may be less successful compared with WES in detecting rare variants with large effect size, it can be useful in highlighting genomic regions containing other types of common genetic events (structural, noncoding, or regulatory) that may act " in aggregate" as modifiers [33].…”

“…However, in the current study our primary aim is to detect rare variants with predicted damaging effect regardless of the segregation pattern. It is perhaps unsurprising that none of the candidate genes revealed here in the multi-incident families existed in regions overlapping with what we have previously reported [36]. This is anticipated, given that genetic and allelic heterogeneity, reduced penetrance and variable expressivity are all factors known to influence the impact of genetic changes, an issue that has been increasingly recognized in complex disorders [33,37].…”

“…Assuming homozygous inheritance, we have previously analyzed all of the multi-incident families (Table S9) with apparently unaffected parents for regions of homozygosity shared only between affected individuals within or across families [36]. In our previous work the intention was to detect genomic regions of homozygosity that are likely to contain causal variants.…”

Appraisal of clinical practice guidelines for the management of attention deficit hyperactivity disorder (ADHD) using the AGREE II Instrument: A systematic review

“…Attention deficit hyperactivity disorder [1,2] or Attention-Deficit/ Hyperactivity Disorder [3,4] (ADHD), is a chronic neurodevelopmental disorder characterized by developmentally inappropriate levels of hyperactivity-impulsivity and/or inattention [1–9]. ADHD is clinically and genetically heterogeneous with multiple possible etiologies and frequent neuropsychiatric comorbidities [10,11].…”

Genome-Wide Homozygosity Mapping Reveals Genes Associated With Cognitive Ability in Children From Saudi Arabia

“…We also hypothesized that these regions would be placed in-between common and rare variants on the continuum of effect sizes and that elevated levels of homozygosity (and allelic ROHs) would increase our statistical power to detect such effects even in a sample of modest size. This hypothesis is contextualized by 1) observations that long ROHs are enriched for deleterious variation that amplify the effects of mildly deleterious variants that exist in a homozygous state (Szpiech et al, 2013) and 2) recent successes in the homozygosity mapping of neurodevelopmental attention-deficit/hyperactivity disorder in a small sample of Saudi siblings with attention-deficit/hyperactivity disorder, which identified several new candidates for the disorder in a sample of limited size (Shinwari et al, 2017). Therefore, by capitalizing on the unique nature of the sample from the consanguineous population of KSA, recent advances in model-based identification of long tracts of homozygosity (Ceballos et al, 2018a; Ceballos et al, 2018b), and quantification of latent cognitive ability trait estimates via structural equation modeling, we sought to perform a GWAS and homozygosity mapping of cognitive ability in a sample of children from Saudi Arabia using a genotyping platform with increased exonic coverage, enabling the identification of long genic ROHs.…”