New GWAS of ADHD captures convergence of common and rare variants in SORCS3

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New GWAS of ADHD based on 38,691 cases and >180k controls. Congrats! @DemontisDitte, @AndersBorglum, @iPSYCHdk and collaborators. 🧵 nature.com/articles/s41588-022-01285-8

Despite a higher prevalence (~5%) than schizophrenia (~1%), ADHD GWAS lagged far behind Schizophrenia GWAS. The latest GWAS of schizophrenia included >76k cases. twitter.com/doctorveera/status/1513349006750994441?s=20&t=DYhRtjXpXU92HOK-jDQcSw

Two major reasons: 1. ADHD is a childhood onset condition and most of the biobanks (both volunteers based and hospital based) are skewed towards older individuals.

2. Doctors started giving ADHD (and ASD) diagnoses only in the past two decades. So, it's rare for those with ADHD born in 1980s and before to have received a proper diagnosis. (it's important to factor this when including adults as controls) link.springer.com/article/10.1007/s00228-012-1265-y

So, ADHD sample size didn't take off as quickly as other psychiatric disorders such as schizophrenia, bipolar disorder and depression.

Thanks to @iPSYCHdk, which is based on a Danish birth cohort and comprise only those born after 1980. Hence it became a major biobank source for individuals with ADHD and ASD diagnoses. medrxiv.org/content/10.1101/2020.11.30.20237768v1.full

First GWAS of ADHD was published in 2018 based on 20k cases and 35k controls by the iPSYCH and PGC researchers with a major contribution from iPSYCH. nature.com/articles/s41588-018-0269-7

Five years later, the authors have doubled this sample size with, again, the majority of cases coming from the iPSYCH cohort. nature.com/articles/s41588-022-01285-8

The new larger sample size has more than doubled the number of GWAS loci, brought clarity to many secondary analysis in terms of enrichment for brain expressed genes, strong genetic correlations with other psychiatric, addiction and cognitive traits.

The polygenic score using new sample size starkly captures the negative relationship with cognitive functions like reading skills, verbal reasoning and importantly attention skills (as the name suggests).

My favorite finding though is converge of common and rare variants at some of the GWAS loci. For example, the authors highlight a locus in chromosome 10 where both common and rare variants in SORCS3 increase the risk of ADHD.

SORCS3 codes for transmembrane receptor protein expressed specifically in brain, has some important synaptic function and has some interesting links to Alzheimer's. Mice lacking SORCS3 show behavioral abnormalities including loss of fear. journals.plos.org/plosone/article?id=10.1371/journal.pone.0075006

Overall the current GWAS represents a great progress in our understanding of genetic architecture of ADHD. Congrats again to all the authors, especially my PhD supervisor @DemontisDitte who has been recently promoted to Professor 👏 👏 biomed.au.dk/display/artikel/inaugural-lecture-by-ditte-demontis