Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function

Rigbi, Amihai; Kanyas, Kyra; Yakir, A; Greenbaum, Lior; Pollak, Yehudah; Ben-Asher, Edna; Lancet, Doron; Kertzman, Semion; Lerer, Bernard

doi:10.1111/j.1601-183x.2007.00329.x

Cited by 46 publications

(53 citation statements)

References 33 publications

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“…Among many interesting examples of proteins at the network periphery that may be under positive selection are the protein encoded by the CHRNA5 (ENSG00000169684) gene, neuronal acetyl-choline receptor subunit ␣-5; this integral membrane protein is involved in neuronal processes likely to be under ongoing adaptation, and CHRNA5 was recently associated with several cognitive performance criteria (34). Another protein, the Ficolin-3 protein encoded by the FCN3 gene (ENSG00000142748), is a secreted protein that exerts lectin activity and is presumably involved in innate immunity through binding to bacterial lipopolysaccharides (35).…”

Section: Discussionmentioning

confidence: 99%

Positive selection at the protein network periphery: Evaluation in terms of structural constraints and cellular context

Kim

Korbel

Gerstein

2007

Proc. Natl. Acad. Sci. U.S.A.

132

128

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Because of recent advances in genotyping and sequencing, human genetic variation and adaptive evolution in the primate lineage have become major research foci. Here, we examine the relationship between genetic signatures of adaptive evolution and network topology. We find a striking tendency of proteins that have been under positive selection (as compared with the chimpanzee) to be located at the periphery of the interaction network. Our results are based on the analysis of two types of genome evolution, both in terms of intra-and interspecies variation. First, we looked at single-nucleotide polymorphisms and their fixed variants, single-nucleotide differences in the human genome relative to the chimpanzee. Second, we examine fixed structural variants, specifically large segmental duplications and their polymorphic precursors known as copy number variants. We propose two complementary mechanisms that lead to the observed trends. First, we can rationalize them in terms of constraints imposed by protein structure: We find that positively selected sites are preferentially located on the exposed surface of proteins. Because central network proteins (hubs) are likely to have a larger fraction of their surface involved in interactions, they tend to be constrained and under negative selection. Conversely, we show that the interaction network roughly maps to cellular organization, with the periphery of the network corresponding to the cellular periphery (i.e., extracellular space or cell membrane). This suggests that the observed positive selection at the network periphery may be due to an increase of adaptive events on the cellular periphery responding to changing environments.protein structure ͉ network centrality ͉ single-nucleotide change ͉ copy number variant ͉ structural variant W ith the advent of genomic sequence data and, more recently, large-scale genetic variation data (1, 2), it has become possible to examine genes or genomic regions for signs of recent evolutionary adaptation in our genome, characterized as signatures of positive selection (3, 4). Typically, tests for positive selection predict adaptation by testing and rejecting the hypothesis of neutral mutation (5) or variation for a given genomic region.Despite considerable advances in the field of genetics, the actual molecular relationship of recent evolutionary events with biophysical properties of associated proteins such as structural characteristics and network connectivity (i.e., protein interactions) has as yet not been studied in detail. Understanding the extent of recent mutations, polymorphisms, and adaptation beyond their effect on the gene level is crucial because most complex cellular processes only come about through the interplay and interactions of many different proteins. On the other hand, although recent proteomic surveys have suggested that proteins with many interaction partners are subject to considerable structural constraints, the connection with human genome variation has not yet been considered. Thus, by combining knowledge fr...

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Section: Discussionmentioning

confidence: 99%

Positive selection at the protein network periphery: Evaluation in terms of structural constraints and cellular context

Kim

Korbel

Gerstein

2007

Proc. Natl. Acad. Sci. U.S.A.

132

128

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“…30,31 CHRNA2 is a broadly-expressed subunit of nicotinic acetylcholine receptors. 32 In addition to its role in nicotine dependence and neurocognitive functioning, 33,34 CHRNA2 is located in a region of chromosome 8p that is suggested to contribute to psychiatric and neurodegenerative disorders. 35 Interestingly, nominal differential methylation of CHRNA2 was recently reported in monozygotic twins discordant for psychosis.…”

Section: Subject Enrollment Subjects Were Recruited From the Specialmentioning

confidence: 99%

DNA methylation in neonates born to women receiving psychiatric care

et al. 2012

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“…81,188,189 Before dependence on nicotine is established, factors such as these (as well as genetic factors) influence the likelihood of initiating smoking (SI) which is a prerequisite for ND to develop. A further complexity that must be taken into account is that personality, psychopathology and cognitive function are themselves influenced by genetic factors.…”

Section: General Overviewmentioning

confidence: 99%

“…209 We suggest that the improvement by nicotine of cognitive function in these domains may predispose young women who initiate cigarette smoking to maintain the habit. 209 Subsequently, Rigbi et al 189 showed that the performance on the relevant test measures (for example, response inhibition) is modified by specific variants in nAChR genes, mostly in CHRNA4, CHRNA7 and CHRNB3 but also in other nAChR genes. 189 nAChR genes, neuroticism and ND A connection between neuroticism and smoking is well established, both in adults and adolescents.…”

Section: General Overviewmentioning

confidence: 99%

“…209 Subsequently, Rigbi et al 189 showed that the performance on the relevant test measures (for example, response inhibition) is modified by specific variants in nAChR genes, mostly in CHRNA4, CHRNA7 and CHRNB3 but also in other nAChR genes. 189 nAChR genes, neuroticism and ND A connection between neuroticism and smoking is well established, both in adults and adolescents. 188,194,219 Neuroticism is associated with manifestations of anxiety and depression.…”

Section: General Overviewmentioning

confidence: 99%

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Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function

Cited by 46 publications

References 33 publications

Positive selection at the protein network periphery: Evaluation in terms of structural constraints and cellular context

Positive selection at the protein network periphery: Evaluation in terms of structural constraints and cellular context

DNA methylation in neonates born to women receiving psychiatric care

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

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