Early manifestations of genetic liability for ADHD, autism and schizophrenia at ages 18 and 24 months

Abstract

Pregnant women resident in Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 were invited to take part in the study. The initial number of pregnancies enrolled is 14,541 (for these at least one questionnaire has been returned or a "Children in Focus" clinic had been attended by 19/07/99). Of these initial pregnancies, there was a total of 14,676 foetuses, resulting in 14,062 live births and 13,988 children who were alive at 1 year of age. When the oldest children were approximately 7 years of age, an attempt was made to bolster the initial sample with eligible cases who had failed to join the study originally. These individuals were not included in our analyses as we focussed on outcomes prior to age 7 years.The sample is relatively homogeneous in regard to ethnicity (approximately 98% White): all participants are from the Bristol area in the United Kingdom. 1 Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/.Further details of the study, measures and sample can be found elsewhere. [1][2][3] Generating polygenic scoresIn total 9912 ALSPAC children were genotyped using the Illumina HumanHap500-quad genotyping array. Individuals were excluded on the basis of gender mismatches; minimal or excessive heterozygosity, disproportionate levels of individual missingness (>3%), insufficient sample replication (IBD <0.8), non-European ancestry (assessed by multidimensional scaling analysis and compared with Hapmap II) and cryptic relatedness (IBD > 0.1). SNPs were excluded based on minor allele frequency (<1%), call rate (<95%) or evidence for violations of Hardy-Weinberg equilibrium (P < 5E-7). Imputation was conducted by the ALSPAC team using Impute V2.2.2 against the 1000 genomes reference panel (Phase 1, Version 3: all polymorphic SNPs excluding singletons), using all 2186 reference haplotypes (including non-Europeans).SNPs were subsequently filtered based on minor allele frequency (<1%) and imputation quality (INFO<0.8). Sensitivity analyses utilised the top 10 principal components (in-line with previously work 4 ) generated using PLINK 5 --pca command (https://gist.github.com/explodecomputer/ab3552ee06b5c0df76139fc587373599). Following quality control and limiting individuals to one child per family, genetic data were available for N=7975.Genome-wide association study (GWAS) were filtered to remove SNPs that were palindromic, insertions/deletions, non-autosomal, INFO score <0.8, missing in N>1 study and duplicates (https://github.com/ricanney).

Polygenic risk scores and early manifestations of attention‐deficit/hyperactivity disorder

“…For example, more research is needed on how PRS associates with precursors and early markers of ADHD. Second, the study by Riglin et al (2022) Second, because of a lack of ancestral diversity in currently available GWAS, individuals were excluded from the analyses on the basis of non-European ancestry, which limits generalisability. Investments are needed to perform large-scale GWASs in globally diverse populations.…”

“…Third, while PRSs are useful for studying correlations, they cannot be taken as evidence of causality. Riglin et al (2022) correctly point out that they cannot differentiate whether motor development and temperament lie on the causal pathway between genetic liability to neurodevelopmental conditions and later neurodevelopmental conditions, if these associations arise independently as the result of (horizontal) pleiotropy, or whether the associations reflect an early manifestation of neurodevelopmental conditions. Implementation of sophisticated study designs and analyses will probably help uncover the mechanisms underlying identified PRS associations.…”

“…Implementation of sophisticated study designs and analyses will probably help uncover the mechanisms underlying identified PRS associations. As suggested by Riglin et al (2022), research could investigate whether parental risk alleles for neurodevelopmental conditions (e.g., ADHD, autism and schizophrenia) are associated with differences in ratings of their children and whether un-transmitted risk alleles using parent-child trios contribute to "genetic nurture" effects. Mendelian Randomization methods can also complement findings from more standard PRS association analyses to strengthen causal inference, in particular when based on rigorous MR analyses with smaller numbers of highly significant variants using methods designed to account for pleiotropic bias.…”

“…Tobarra-Sanchez et al (2022) andRiglin et al (2022) discuss their main findings in context of three important limitations. These limitations are important to address in future research as they constrain a broader use of PRS in psychiatric research and clinical contexts.First, PRS for ADHD and other neurodevelopmental conditions at present explain only a small fraction of variance in ADHD and early manifestations of ADHD, and is therefore a weak instrument.While larger GWAS samples will increase the predictive ability, ADHD PRS will likely never, on their own, be able to predict future diagnoses in a meaningful way.…”

“…two publications byTobarra-Sanchez et al (2022) andRiglin et al (2022) provides novel insight into associations between polygenic risk scores and early manifestations of ADHD. In the future, the combined use of aspects of early development, other relevant clinical information and PRS may be used to improve outcome prediction and aid clinical decision-making.…”