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Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

ABSTRACT: Objective:The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder. Method:We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions. Results:Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder. Conclusion:These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.

SUBMITTER: Sengupta SM

PROVIDER: S-EPMC7391869 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

Sengupta Sarojini M SM Grizenko Natalie N Fortier Marie-Ève MÈ Ter-Stepanian Marina M Joober Ridha R

Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent 20200801 3

<h4>Objective</h4>The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between ...[more]

PMID: 32774401

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Project description:Neurocognitive heterogeneity is increasingly recognized as a valid phenomenon in ADHD, with most estimates suggesting that executive dysfunction is present in only about 33%-50% of these children. However, recent critiques question the veracity of these estimates because our understanding of executive functioning in ADHD is based, in large part, on data from single tasks developed to detect gross neurological impairment rather than the specific executive processes hypothesized to underlie the ADHD phenotype. The current study is the first to comprehensively assess heterogeneity in all three primary executive functions in ADHD using a criterion battery that includes multiple tests per construct (working memory, inhibitory control, set shifting). Children ages 8-13 (M?=?10.37, SD?=?1.39) with and without ADHD (N?=?136; 64 girls; 62% Caucasian/Non-Hispanic) completed a counterbalanced series of executive function tests. Accounting for task unreliability, results indicated significantly improved sensitivity and specificity relative to prior estimates, with 89% of children with ADHD demonstrating objectively-defined impairment on at least one executive function (62% impaired working memory, 27% impaired inhibitory control, 38% impaired set shifting; 54% impaired on one executive function, 35% impaired on two or all three executive functions). Children with working memory deficits showed higher parent- and teacher-reported ADHD inattentive and hyperactive/impulsive symptoms (BF10?=?5.23?×?104), and were slightly younger (BF10?=?11.35) than children without working memory deficits. Children with vs. without set shifting or inhibitory control deficits did not differ on ADHD symptoms, age, gender, IQ, SES, or medication status. Taken together, these findings confirm that ADHD is characterized by neurocognitive heterogeneity, while suggesting that contemporary, cognitively-informed criteria may provide improved precision for identifying a smaller number of neuropsychologically-impaired subtypes than previously described.

Project description:BackgroundGastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.MethodsWe did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.FindingsOur GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.InterpretationOur findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.FundingGerman Research Foundation (DFG).

Dataset Information

Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

Publications

Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

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