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Esteller-Cucala et al. 2020 — ADHD evolutionary genomics

🔬ResearchPeer-reviewed

3 min read

Citation

Esteller-Cucala, P., Maceda, I., Børglum, A.D., Demontis, D., Faraone, S.V., Cormand, B., & Lao, O. (2020). “Genomic analysis of the natural history of attention-deficit/hyperactivity disorder using Neanderthal and ancient Homo sapiens samples.” Scientific Reports, 10, 65322. doi:10.1038/s41598-020-65322-4. Open Access.

Key findings

  • ADHD-associated alleles have been steadily decreasing in frequency since Paleolithic times in European populations. The trait-associated variants were more common in ancient hunter-gatherers than in modern humans.
  • Neanderthal-introgressed alleles are enriched in ADHD risk variants — Neanderthals carried more of the DNA associated with ADHD-like traits than modern humans do today.
  • The decline in ADHD-associated alleles is not explained by African admixture or Neanderthal introgression — the selective pressure against these alleles is genuine and long-standing.
  • ADHD-associated alleles are enriched in loss-of-function intolerant genes, supporting the role of selective pressures acting on this phenotype.
  • Results are compatible with the mismatch theory — the idea that traits once adaptive in an ancient environment become maladaptive when that environment changes — but the timescale is much older than previous hypotheses suggested. The selective pressure predates the Paleolithic/Neolithic transition and extends back into archaic human populations.

Why this matters beyond ADHD

The paper does not directly address autism, but it matters for this wiki because:

  1. It establishes a methodological template. The approach — using archaic and ancient DNA to trace the evolutionary trajectory of neurodevelopmental trait variants — is exactly what Pauly et al. (2024) then applied to autism. The two papers share intellectual DNA (and some actual genomic databases).

  2. It makes the mismatch theory empirically tractable. Rather than speculating about whether ADHD traits were “useful for hunter-gatherers,” this study actually measures allele frequencies across time. The finding that the selective pressure is older than the agricultural revolution complicates the standard narrative.

  3. ADHD and autism co-occur. The Litman/Sauerwald (2025) phenotypic classes show that ADHD is specifically enriched in the “Social/behavioral” class of autism. Understanding the evolutionary trajectory of ADHD-associated variants is therefore directly relevant to understanding a subset of autistic people.

  4. It supports the neurodiversity framing at a deep level. If ADHD-associated variants have been under long-standing selective pressure but have not been eliminated — indeed, they were more common in archaic populations — then the traits they produce are part of the normal range of human cognitive variation, shaped by hundreds of thousands of years of evolutionary history. The same argument applies, mutatis mutandis, to autism.

Method in brief

Largest available GWAS meta-analysis for ADHD (>20,000 ADHD, >35,000 controls). Allele frequencies compared across: archaic humans (Neanderthal, Denisovan), ancient European populations (Palaeolithic, Mesolithic, Neolithic, Bronze Age), and modern Europeans. Approximate Bayesian computation with deep learning for adaptation detection. Singleton density scores to test for recent selective sweeps.

Limitations

  • European populations only. The evolutionary trajectory may differ in East Asian, African, or other populations.
  • GWAS-derived alleles are common variants of small effect. Rare variants and structural variation are not captured.
  • “ADHD” as defined by modern diagnostic criteria may not map cleanly onto the phenotype that was under selection in ancient populations. The same alleles may have produced different presentations in different environments.

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