Dataset Information

Genetics of cognition in epilepsy.

ABSTRACT: With the completion of the Human Genome Project and the advent of more advanced sequencing platforms capable of high throughput genotyping at reduced cost, research on the genetics/genomics of cognition has expanded rapidly over the past several decades. This has been facilitated even further by global consortia including HapMap, 1000 Genomes Project, ENCODE, and others, which have made information regarding genetic variation and genomic functional elements readily available to all researchers. Thus, the goal of this Targeted Review is not to provide an exhaustive review of the existing literature on the role of genetic factors in cognition. Rather, we will highlight some of the most consistent findings in this field, review the research in epilepsy to date, and provide a background within which to set forth unique opportunities epilepsy may provide to further elucidate the role of genetics in cognition.

SUBMITTER: Busch RM

PROVIDER: S-EPMC4268334 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Genetics of cognition in epilepsy.

Busch Robyn M RM Najm Imad I Hermann Bruce P BP Eng Charis C

Epilepsy & behavior : E&B 20140625

With the completion of the Human Genome Project and the advent of more advanced sequencing platforms capable of high throughput genotyping at reduced cost, research on the genetics/genomics of cognition has expanded rapidly over the past several decades. This has been facilitated even further by global consortia including HapMap, 1000 Genomes Project, ENCODE, and others, which have made information regarding genetic variation and genomic functional elements readily available to all researchers. ...[more]

PMID: 24973143

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Project description: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.

Project description:ObjectiveBirth weight is an important indicator of prenatal environment, and subtle variations of birth weight within the normal range have been associated with differential risk for cognitive and behavioral problems. Therefore, we aimed to determine if there are differences in birth weight between full-term children with uncomplicated new/recent-onset epilepsies and typically developing healthy controls. We further examined the relationships between birth weight and childhood/adolescent cognition, behavior, and academic achievement.MethodsOne hundred eight children with new-onset/recent-onset epilepsy and 70 healthy controls underwent neuropsychological assessment. All participants were born full-term (>37 weeks) without birth complications. Parents were interviewed regarding their child's gestation, birth, and neurodevelopmental history.ResultsBirth weight of children with epilepsy was significantly lower than healthy controls (p = 0.023). Whereas birth weight (covaried with age, sex, handedness, and mother's education) was significantly associated with cognition in controls in multiple domains (intelligence, language, aspects of academic achievement), this relationship was absent in children with epilepsy. Birth weight was not associated with clinical epilepsy variables (age of onset, epilepsy syndrome) and was not predictive of a variety of other academic or psychiatric comorbidities of epilepsy.SignificanceAlthough the origin of lower birth weight in children with epilepsy is unknown, these findings raise the possibility that abnormal prenatal environment may affect childhood-onset epilepsy. Furthermore, the positive relationship between birth weight and cognition evident in healthy controls was disrupted in children with epilepsy. However, birth weight was not related to academic and psychiatric comorbidities of childhood epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Dataset Information

Genetics of cognition in epilepsy.

Publications

Genetics of cognition in epilepsy.

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