Toward Robust Functional Neuroimaging Genetics of Cognition
Name
8778.full.pdf
Description
Published version
Size
770.43 KB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Uddén, Julia
Hultén, Annika
Bendtz, Katarina
Mineroff, Zachary
Kucera, Katerina S
Vino, Arianna
Fedorenko, Evelina
Hagoort, Peter
Fisher, Simon E
Date Issued
2019
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Version
Final published version
Abstract
A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10-100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1523/JNEUROSCI.0888-19.2019
