Sex-dependent association of common variants of microcephaly genes with brain structure

Rimol, Lars M.; Agartz, Ingrid; Djurovic, Srdjan; Brown, Andrew A.; Roddey, J. Cooper; Kähler, Anna K.; Mattingsdal, Morten; Athanasiu, Lavinia; Joyner, Alexander H.; Schork, Nicholas J.; Halgren, Eric; Sundet, Kjetil; Melle, Ingrid; Dale, Anders M.; Andreassen, Ole A.

doi:10.1073/pnas.0908454107

Cited by 105 publications

(97 citation statements)

References 38 publications

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“…However, as no interaction with diagnosis was found in the current study, and the direction of effect was the same for the control group, those with schizophrenia and those with bipolar disorder (little can be said about the 'other psychosis' group, as it contained only one minor allele carrier), the present results suggest this variant acts independently of any neuropsychiatric disorder. Similar findings have been obtained with other genes controlling important brain phenotypes (Rimol et al, 2010).…”

Section: Discussionsupporting

confidence: 89%

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

et al. 2012

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* These authors contributed equally.As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.

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Section: Discussionsupporting

confidence: 89%

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

et al. 2012

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“…These findings clearly support the idea that normal variants (polymorphisms) of these genes are implicated in normal variation in brain structure, because they probably control the number of symmetric divisions of the neuroepithelial cells during embryogenesis (Bond and Woods 2006;Zhong et al 2006) resulting in variation in brain size (Caviness et al 1995;Dediu and Ladd 2007). Given the apparent region specificity of the effects of normal polymorphisms on cortical area 8 (Rimol et al 2010), it is not improbable to suggest that the derived haplogroups of ASPM and Microcephalin can affect brain networks involved in the acquisition, processing, or both of linguistic tone. In fact, association studies focusing specifically on these haplogroups and brain areas putatively involved in tone are a natural next step.…”

Section: ϫ5supporting

confidence: 60%

“…The actual mechanisms through which these genes could influence the acquisition, processing, or both of linguistic tone are currently not clear, but several promising hints do exist. It is clear that deleterious mutations of ASPM and Microcephalin are causes of primary microcephaly (Cox et al 2006;Gilbert et al 2005;Woods 2004), as discussed above briefly, and it also has been recently shown that polymorphisms in Microcephalin are associated with normal variation in the cranial volume in a sample of Chinese males (Wang et al 2008), whereas polymorphisms in both genes show a sex-specific association with brain volume and cortical surface area in a combined Norwegian-North American sample (Rimol et al 2010). These findings clearly support the idea that normal variants (polymorphisms) of these genes are implicated in normal variation in brain structure, because they probably control the number of symmetric divisions of the neuroepithelial cells during embryogenesis (Bond and Woods 2006;Zhong et al 2006) resulting in variation in brain size (Caviness et al 1995;Dediu and Ladd 2007).…”

Section: ϫ5mentioning

confidence: 95%

“…In 2005, the existence of a "derived" haplogroup, one for each gene, was reported Mekel-Bobrov et al 2005), having a skewed geographical distribution and reportedly under recent or ongoing natural selection. 7 The phenotypic effects of these derived haplogroups are seemingly not major and do not seem to be related to, for example, variation in intelligence or head size in the normal population (Mekel-Bobrov et al 2007;Woods et al 2006) or to the incidence of schizophrenia (Rivero et al 2006); however, there seems to be an association between Microcephalin and cranial volume in normal Chinese males (Wang et al 2008) and an independent finding of a sex-specific association between these two genes and normal variation in brain anatomy (Rimol et al 2010).…”

Section: Linguistic Tone As Biased By Aspm and Microcephalinmentioning

confidence: 99%

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Are Languages Really Independent from Genes? If Not, What Would a Genetic Bias Affecting Language Diversity Look Like?

Dediu

2011

Human Biology

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It is generally accepted that the relationship between human genes and language is very complex and multifaceted. This has its roots in the "regular" complexity governing the interplay among genes and between genes and environment for most phenotypes, but with the added layer of supraontogenetic and supraindividual processes defining culture. At the coarsest level, focusing on the species, it is clear that humanspecific-but not necessarily faculty-specific-genetic factors subtend our capacity for language and a currently very productive research program is aiming at uncovering them. At the other end of the spectrum, it is uncontroversial that individual-level variations in different aspects related to speech and language have an important genetic component and their discovery and detailed characterization have already started to revolutionize the way we think about human nature. However, at the intermediate, glossogenetic/population level, the relationship becomes controversial, partly due to deeply ingrained beliefs about language acquisition and universality and partly because of confusions with a different type of genelanguages correlation due to shared history. Nevertheless, conceptual, mathematical and computational models-and, recently, experimental evidence from artificial languages and songbirds-have repeatedly shown that genetic biases affecting the acquisition or processing of aspects of language and speech can be amplified by population-level intergenerational cultural processes and made manifest either as fixed "universal" properties of language or as structured linguistic diversity. Here, I review several such models as well as the recently proposed case of a causal relationship between the distribution of tone languages and two genes related to brain growth and development, ASPM and Microcephalin, and I discuss the relevance of such genetic biasing for language evolution, change, and diversity. Abstract It is generally accepted that the relationship between human genes and language is very complex and multifaceted. This has its roots in the "regular" complexity governing the interplay among genes and between genes and environment for most phenotypes, but with the added layer of supraontogenetic and supra-individual processes defining culture. At the coarsest level, focusing on the species, it is clear that human-specific-but not necessarily faculty-specific-genetic factors subtend our capacity for language and a currently very productive research program is aiming at uncovering them. At the other end of the spectrum, it is uncontroversial that individual-level variations in different aspects related to speech and language have an important genetic component and their discovery and detailed characterization have already started to revolutionize the way we think about human nature. However, at the intermediate, glossogenetic/population level, the relationship becomes controversial, partly due to deeply ingrained beliefs about language acquisition and universality and partly because of confusi...

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“…For example, two candidate gene studies recently identified SNPs in microcephaly genes (29) and MECP2 (30) that explained a small but statistically significant amount of variation in total cortical surface area between human individuals and were replicated in independent study populations.…”

Section: −8mentioning

confidence: 99%

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

Bakken

Roddey

Djurovic

et al. 2012

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

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Visual cortical surface area varies two-to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P combined = 3.2 × 10 −8). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10 −9) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5′ UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.allometry | brain morphometry | imaging genetics | V1

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Sex-dependent association of common variants of microcephaly genes with brain structure

Cited by 105 publications

References 38 publications

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

Are Languages Really Independent from Genes? If Not, What Would a Genetic Bias Affecting Language Diversity Look Like?

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

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