The role of genetic variation in the causation of mental illness: an evolution-informed framework

Uher, Rudolf

doi:10.1038/mp.2009.85

Cited by 171 publications

(127 citation statements)

References 122 publications

(166 reference statements)

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“…The reasons for this paradox remain unclear and have sparked much debate and speculation. Among possible explanations are balancing selection favoring genotype diversity; advantage for those who carry the allele but do not get sick; changing environments that expose or protect cryptic variation; or quick replenishment by new mutations, in view of the possibility that disruption of thousands of different genes may be able to lead to disease [20, 21, 22]. The results of genome-wide association studies (GWAS) that we will discuss below support this highly polygenic architecture.…”

Section: Introductionmentioning

confidence: 94%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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Section: Introductionmentioning

confidence: 94%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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“…Although expectations were high, the genome-wide approach has not yet found the genes accounting for the high heritability estimates of most psychiatric disorders obtained in twin studies. In search for this missing heritability, it has been posited that at least part of it must be hidden in gene-environment interactions (Uher, 2009). Gene-environment interactions are not conditional on the presence of main effects.…”

Section: Discussionmentioning

confidence: 99%

Variation in the Glucocorticoid Receptor Gene at rs41423247 Moderates the Effect of Prenatal Maternal Psychological Symptoms on Child Cortisol Reactivity and Behavior

Velders

Dieleman

Cents

et al. 2012

Neuropsychopharmacol

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Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic-pituitary-adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p ¼ 0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta À2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene-environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.

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“…Indeed, a role of PEDF genetic polymorphisms has been observed in numerous dis- eases, such as AMD, myopic choroidal neovascularization, insulin resistance and type 2 diabetes. On the grounds of common disease/common variant (CDCV) model, common genetic variants of small to moderate effect underlie the risk of common disorders or diseases (Uher 2009). Furthermore, both abnormal angiogenesis in a multitude of ophthalmic diseases as mentioned above and obesity-related insulin resistance are related to atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

The T Allele of rs8075977 in the 5′-Flanking Region of the PEDF Gene Is Associated with Reduced Risk of Coronary Artery Disease in Elderly Chinese Men

Guo

Wang

et al. 2017

Tohoku J. Exp. Med.

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Coronary artery disease (CAD) is a multifactorial disease with a genetic component. Pigment epitheliumderived factor (PEDF) exerts anti-inflammatory, anti-oxidant, anti-thrombotic, and anti-angiogenic effects and thus has received increasing attention as a sensitive biomarker of atherosclerosis and CAD. To explore the potential association between PEDF single nucleotide polymorphisms (SNPs) and CAD, we performed this case-control study of consecutive elderly Chinese Han male patients (n = 416) and age-matched male controls (n = 528) without a history of CAD or electrocardiographic signs of CAD. The enrolled CAD patients (age ≥ 60 years) are not biologically related. A tag approach was used to examine 100% of common variations in the PEDF gene (r 2 ≥ 0.8, minor allele frequency > 0.1). PEDF tag SNPs (tSNPs) were selected using the HapMap Data-CHB which describes the common patterns of human DNA sequence variation and Tagger program. SNPs were genotyped using ligase detection reaction (LDR). Seven tSNPs (rs8075977, rs11658342, rs1136287, rs12603825, rs12453107, rs6828 and rs11078634) were selected. Among them, only one SNP, rs8075977 (C/T) located in the 5'-flanking region, showed the significant effect on the susceptibility to CAD. The frequency of its T allele was significantly higher in the controls (52.7%) than that in the CAD group (46.2%) (adjusted OR = 0.88, 95% CI: 0.80-0.96; P = 0.005).In conclusion, the T allele of rs8075977 in the 5'-flanking region of the PEDF gene may be protective for CAD. Conversely, the C allele at this variation site is associated with CAD in elderly Chinese Han men.

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The role of genetic variation in the causation of mental illness: an evolution-informed framework

Cited by 171 publications

References 122 publications

Recent Advances in the Genetics of Schizophrenia

Recent Advances in the Genetics of Schizophrenia

Variation in the Glucocorticoid Receptor Gene at rs41423247 Moderates the Effect of Prenatal Maternal Psychological Symptoms on Child Cortisol Reactivity and Behavior

The T Allele of rs8075977 in the 5′-Flanking Region of the PEDF Gene Is Associated with Reduced Risk of Coronary Artery Disease in Elderly Chinese Men

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