PMC:2820181 / 29348-36040 JSONTXT

{"project":"2_test","denotations":[{"id":"20060087-19559598-2044393","span":{"begin":2224,"end":2226},"obj":"19559598"},{"id":"20060087-18339943-2044393","span":{"begin":2224,"end":2226},"obj":"18339943"},{"id":"20060087-19524518-2044393","span":{"begin":2224,"end":2226},"obj":"19524518"},{"id":"20060087-18995821-2044394","span":{"begin":2321,"end":2323},"obj":"18995821"},{"id":"20060087-19446012-2044395","span":{"begin":2834,"end":2836},"obj":"19446012"},{"id":"20060087-18988837-2044396","span":{"begin":3647,"end":3649},"obj":"18988837"},{"id":"20060087-18987709-2044397","span":{"begin":5312,"end":5314},"obj":"18987709"},{"id":"20060087-19539887-2044398","span":{"begin":6522,"end":6524},"obj":"19539887"}],"text":"Discussion\nHere, we applied an innovative functional gene group approach to cognitive ability. Functional gene groups were defined on the basis of shared cellular function of genes, as determined by previous protein identification and data mining for synaptic genes and gene function. Initially, we identified the group of synaptic heterotrimeric G proteins to be associated with cognitive ability in a relatively small sample of 627 subjects. We replicated these findings in an independent large cohort of 1507 subjects.\nAssociation of the group of heterotrimeric G proteins could not be attributed to a single gene or a single SNP, because none of the individual p values came close to genome-wide significance, confirming the importance of focusing on the gene group as the unit of analysis and not on single-SNP effects.\nHeterotrimeric G proteins consist of three subunits (α, β, and γ), for which a total of 33 genes are found in the human genome. Twenty-seven of these are ubiquitously expressed in the synapse. Many of these proteins are also expressed in the nonsynaptic areas of neurons and in other cells inside and outside the brain. Heterotrimeric G proteins are central relay factors between the activation of plasma membrane receptors by extracellular ligands and the cellular responses that these induce. Some signaling molecules in the brain can also activate ionic currents upon binding to ionotropic receptors, but for most signaling molecules no parallel or alternative pathways next to G protein receptor-coupled signaling exist to induce cellular responses. Therefore, heterotrimeric G proteins may be considered a point of convergence; a kind of “signaling bottleneck.” Although alterations in synaptic processes may not be the exclusive explanation for the association of heterotrimeric G proteins with cognitive ability, it is plausible that such alterations prominently affect the properties of neuronal networks in the brain in such a manner that impaired cognition and lower intelligence is observed. Synaptic processes are thought to have a central role in the “real time” processing capacities of the brain—for instance, in discrimination tasks, working memory, attention, and decision making33–35—as well as in adaptations required for “long-term synaptic modulation” in learning and memory.36\nIt is worth noting that the second most significant (although not below the conservative threshold of significance) functional gene group associated with cognitive ability in this study was the group of “transmitter synthesizing and metabolizing proteins,” which includes the COMT and monoamine oxidase A (MAOA [MIM 309850]) genes. Previous studies have systematically pointed to a role of metabolic enzymes in cognitive ability. In fact, the COMT gene has been associated with many different cognitive traits.37 These results suggest that further exploration of a role of the group of transmitter synthesizing and metabolizing proteins may be indicated.\n\nEvaluating the Combined Effect of Multiple Genes in Functional Gene Groups\nThe functional gene group approach may also prove fruitful for other complex traits or common disorders that are potentially influenced by many genes of small effect. One of the main assumptions of current GWAS is that common diseases are caused by at least a few common genetic variants of relatively large effect (the common disease, common variant [CDCV] hypothesis). If this assumption is not met (e.g., many common alleles with small effect, genetic heterogeneity), GWAS will not work, because in different individuals different variants will account for a disease status or trait level.38 However, if these different variants share a common molecular function, thus sustaining a common biological process, focusing on their combined effect will still be a valuable approach. The functional gene group approach may thus be able to detect genes even when there is large genetic heterogeneity at the SNP level, as long as the many alleles of small effect share a common function in a biological process.\nUnlike previous methods, the functional gene group approach does not rely on post hoc formulation of pathways or networks, but instead takes a hypothesis-driven approach by directly testing functional gene groups. This is opposed to the commonly followed strategy in which the most significant SNPs from a genome-wide association analysis are annotated to search for possible biological pathways associated with the trait. Although this may prove a successful strategy, it will not detect any pathways or functional networks of genes in which most genes are of small and equal effect size, because it focuses initially on SNPs with the largest effects. The applied permutation procedure renders the functional gene group analysis independent of the number of SNPs per gene, of the number of genes per pathway or functional group, and of gene differences in LD structure. Functional gene group analysis may be further preferred because it circumvents the multiple-testing problem and because effect sizes are likely to be increased in comparison to single-SNP effects (because these are now a function of the combined effect, rather than of effects of single genes). This approach may therefore aid in resolving the “case of the missing heritability.”15 It should be noted, however, that the effect size as estimated in the current study explained 3.3% of the observed variation in cognitive ability, which is considered large in comparison to effects of single genes for cognitive ability but is still modest in terms of estimated heritability of cognitive ability. Additional pathways or functional gene groups are therefore also likely to contribute to variation in cognitive ability.\nTo our knowledge, this is the first study reporting on a functional role of synaptic heterotrimeric G proteins in cognitive ability, and it thereby directs future research into the genetic basis of cognitive ability toward synaptic signaling processes. At the same time, these results underscore the notion that pathway analysis or group analysis is more informative as the unit of analysis than is single-SNP analysis, because it is directly related to biological function. The functional gene group approach adapted in this study relies on grouping genes according to similar cellular function on the basis of extensive lab experiments (whole-synapse analyses and solubilized preparations) and data mining. This functional gene group approach complements existing methods16 and may also be useful in identifying etiological factors underlying complex diseases for which classic, genome-wide, SNP-by-SNP analysis has been unsuccessful so far."}