A significant enrichment that is not: spatial nulls, co-expression, and the imaging transcriptomics of EEG alpha-power genetics

Abstract

Background. Imaging transcriptomics routinely asks whether a trait-associated gene set is over-expressed in a region of interest, and the field standard is to guard that inference with a spatial-autocorrelation-preserving spin test. Electroencephalographic (EEG) oscillatory power is among the most heritable human neurophysiological traits, and the cortical generators of the alpha rhythm have been characterised independently from resting-state magnetoencephalography - making this a natural test bed both for asking whether trait genetics is regionally organised, and for asking what such a test actually establishes. Objective. To test whether alpha-associated genetic signal is spatially enriched in the cortical generators of the alpha rhythm, and to evaluate that inference against complementary null models. Methods. MAGMA gene-based analysis of ENIGMA-EEG summary statistics for six phenotypes: central and occipital alpha power, occipital alpha peak frequency, and theta, beta and delta power. Regional transcription was obtained from the Allen Human Brain Atlas (AHBA) with abagen in the Glasser HCP-MMP1.0 atlas, with Schaefer-100 and Yan-600 as sensitivity analyses. Enrichment in the 41 cortical alpha-source regions was quantified with a threshold-free continuous score and a top-100 gene-set composite, and assessed against three complementary nulls: a spin test (10,000 rotations, cross-checked against brainsmash surrogates), a co-expression-aware gene-set null (10,000 matched random gene sets), and a positive control on a known expression gradient. Results. Judged by the field-standard spin test alone, this study would have reported a positive, biologically coherent finding: alpha-power genes are enriched in the cortical alpha generators (continuous p_spin = 0.022; top-100 p_spin = 0.030), with the spin result corroborated by an independent surrogate model (p = 0.018) and the pipeline validated by a positive control (p_spin = 2 x 10^-4). Three further tests dissolve that conclusion. First, it is not band-specific: theta, beta and delta enrich comparably or more strongly (top-100 beta p_spin = 0.011; delta 0.042; continuous theta 0.042). Second, it does not replicate across alpha phenotypes (occipital alpha continuous p_spin = 0.20; alpha peak frequency non-significant, p_spin >= 0.066). Third, against random gene sets of matched size the alpha set is unremarkable (p_geneset = 0.33) - the apparent enrichment is a generic property of arbitrary gene sets in this cortical territory, and is invisible to a spatial-only null. No test survived false-discovery-rate correction across the 24-cell phenotype x score x region-set grid (minimum q = 0.127), and nominal significance did not survive a change of parcellation. Conclusion. EEG alpha-power genetics shows no regionally specific transcriptomic signature in the cortical generators of the rhythm; the weak tendency that is present is shared across frequency bands, consistent with their known genetic correlation. Methodologically, this is a worked demonstration that correcting for spatial autocorrelation is necessary but not sufficient: a spin-significant, surrogate-corroborated, mechanistically plausible enrichment can be fully accounted for by gene-set co-expression. Enrichment claims in imaging transcriptomics should report a gene-set null alongside the spatial null.