Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

Moor, Marleen H. M. de; Berg, Stéphanie Martine van den; Verweij, Karin J. H.; Krueger, Robert F.; Luciano, Michelle; Vasquez, Alejandro Arias; Matteson, Lindsay; Derringer, Jaime; Esko, Tõnu; Amin, Najaf; Gordon, Scott D.; Hansell, Narelle K.; Hart, Amy; Seppälä, Ilkka; Huffman, Jennifer E.; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Gonçalo R.; Adkins, Daniel E.; Agrawal, Arpana; Allik, Jüri; Appel, Katja; Bigdeli, Timothy B.; Busonero, Fabio; Campbell, Harry; Costa, Paul T.; Smith, George Davey; Davies, Gail; Wit, Harriet de; Ding, Jun; Engelhardt, Barbara E.; Eriksson, Johan G.; Fedko, Iryna O.; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard A.; Hartmann, Annette M.; Heath, Andrew C.; Heinonen, Kati; Henders, Anjali K.; Homuth, Georg; Hottenga, Jouke Jan; Iacono, William G.; Janzing, J.G.E.; Jokela, Markus; Karlsson, Robert; Kemp, John P.; Kirkpatrick, Matthew G.; Latvala, Antti; Lehtimäki, Terho; Liewald, David C.; Madden, Pamela A. F.; Magri, Chiara; Magnusson, Patrik K. E.; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E.; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W.; Nauck, Matthias; Ouwens, Klaasjan G.; Palotie, Aarno; Pettersson, Erik; Polašek, Ozren; Qian, Yong; Pulkki-Råbäck, Laura; Raitakari, Olli T.; Realo, Anu; Rose, Richard J.; Ruggiero, Daniela; Schmidt, Carsten Oliver; Slutske, Wendy S.; Sorice, Rossella; Starr, John M.; Pourcain, Beaté St; Sutin, Angelina R.; Timpson, Nicholas J.; Trochet, Holly; Vermeulen, Sita H.; Vuoksimaa, Eero; Widén, Elisabeth; Wouda, Jasper; Wright, Margaret J.; Zgaga, Lina; Porteous, David J.; Minelli, Alessandra; Palmer, Abraham A.; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J.; Räikkönen, Katri; Wilson, James F.; Keltikangas‐Järvinen, Liisa; Bierut, Laura J.; Hettema, John M.; Grabe, Hans J.; Duijn, Cornelia M. van; Evans, David M.; Schlessinger, David; Pedersen, Nancy L.; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W. J. H.; Martin, Nicholas G.; Boomsma, Dorret I.

doi:10.1001/jamapsychiatry.2015.0554

Cited by 292 publications

(227 citation statements)

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“…However, the identification of genes for the typical personality scales has proven difficult (de Moor et al, 2015;Service et al, 2012;van den Berg et al, 2016;Verweij et al, 2010), so very large sample sizes are expected to be required to identify specific variants.…”

Section: Discussionmentioning

confidence: 99%

Individual Differences in Personality Masculinity-Femininity: Examining the Effects of Genes, Environment, and Prenatal Hormone Transfer

et al. 2016

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Males and females score differently on some personality traits, but the underlying etiology of these differences is not well understood. This study examined genetic, environmental, and prenatal hormonal influences on individual differences in personality masculinity–femininity (M-F). We used Big-Five personality inventory data of 9,520 Swedish twins (aged 27 to 54) to create a bipolar M-F personality scale. Using biometrical twin modeling, we estimated the influence of genetic and environmental factors on individual differences in a M-F personality score. Furthermore, we tested whether prenatal hormone transfer may influence individuals’ M-F scores by comparing the scores of twins with a same-sex versus those with an opposite-sex co-twin. On average, males scored 1.09 standard deviations higher than females on the created M-F scale. Around a third of the variation in M-F personality score was attributable to genetic factors, while family environmental factors had no influence. Males and females from opposite-sex pairs scored significantly more masculine (both approximately 0.1 SD) than those from same-sex pairs. In conclusion, genetic influences explain part of the individual differences in personality M-F, and hormone transfer from the male to the female twin during pregnancy may increase the level of masculinization in females. Additional well-powered studies are needed to clarify this association and determine the underlying mechanisms in both sexes.

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Section: Discussionmentioning

confidence: 99%

Individual Differences in Personality Masculinity-Femininity: Examining the Effects of Genes, Environment, and Prenatal Hormone Transfer

et al. 2016

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“…Alternatively, the regression of the repeated measures on genotypes (CNVs or SNPs) and polygenic scores can be carried out using generalized estimating equations to account for the dependency among the measurement measures (e.g., see Minicȃ et al, 2015). The inclusion of repeated measures, where available, in GWAS of neuroticism is a possible way to boost power and extend upon current gene finding efforts (de Moor et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Genetic and Environmental Stability of Neuroticism From Adolescence to Adulthood

et al. 2015

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Longitudinal studies of neuroticism have shown that, on average, neuroticism scores decrease from adolescence to adulthood. The heritability of neuroticism is estimated between 0.30 and 0.60 and does not seem to vary greatly as a function of age. Shared environmental effects are rarely reported. Less is known about the role of genetic and environmental influences on the rank order stability of neuroticism in the period from adolescence to adulthood. We studied the stability of neuroticism in a cohort sequential (classical) twin design, from adolescence (age 14 years) to young adulthood (age 32 years). A genetic simplex model that was fitted to the longitudinal neuroticism data showed that the genetic stability of neuroticism was relatively high (genetic correlations between adjacent age bins >0.9), and increased from adolescence to adulthood. Environmental stability was appreciably lower (environmental correlations between adjacent age bins were between 0.3 and 0.6). This low stability was largely due to age-specific environmental variance, which was dominated by measurement error. This attenuated the age-to-age environmental correlations. We constructed an environmental covariance matrix corrected for this error, under the strong assumption that all age-specific environmental variance is error variance. The environmental (co)variance matrix corrected for attenuation revealed highly stable environmental influences on neuroticism (correlations between adjacent age bins were between 0.7 and 0.9). Our results indicate that both genetic and environmental influences have enduring effects on individual differences in neuroticism.

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“…For DS, we estimated a genetic correlation of 0.588 (SE = 0.242) between GERA and PGC, 0.972 (SE = 0.216) between GERA and UKB, and 0.797 (SE = 0.108) between UKB and PGC. Finally, we estimated a genetic correlation of 1.11 (SE = 0.14) between the measures of neuroticism in the UKB analyses and the summary statistics from a previously published meta-analysis 4 .…”

Section: Genetic Correlationsmentioning

confidence: 99%

“…Twin studies have found that SWB is genetically correlated with depression (characterized by negative affect, anxiety, low energy, bodily aches and pains, pessimism, and other symptoms) and neuroticism (a personality trait characterized by easily experiencing negative emotions such as anxiety and fear) [1][2][3] . Depression and neuroticism have received much more attention than SWB in genetic-association studies, but the discovery of associated genetic variants with either of them has proven elusive 4,5 .…”

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Genetic Associations with Subjective Well-Being Also Implicate Depression and Neuroticism

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Baselmans

Neve

et al. 2015

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We conducted genome-wide association studies of three phenotypes: subjective wellbeing (SWB; N = 298,420), depressive symptoms (DS; N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with SWB, two with DS, and eleven with neuroticism, including two inversion polymorphisms. The two DS loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (| | . ) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.Subjective well-being (SWB)-as measured by survey questions on life satisfaction, positive affect, or happiness-is a major topic of research within psychology, economics, and epidemiology. Twin studies have found that SWB is genetically correlated with depression (characterized by negative affect, anxiety, low energy, bodily aches and pains, pessimism, and other symptoms) and neuroticism (a personality trait characterized by easily experiencing negative emotions such as anxiety and fear) 1-3 . Depression and neuroticism have received much more attention than SWB in genetic-association studies, but the discovery of associated genetic variants with either of them has proven elusive 4,5 .In this paper, we report a series of separate and joint analyses of SWB, depressive symptoms (DS), and neuroticism. Our primary analysis is a genome-wide association study (GWAS) of SWB based on data from 59 cohorts (N = 298,420). This GWAS identifies three loci associated with SWB at genome-wide significance (p < 5×10 -8 ). We supplement this primary analysis with auxiliary GWAS meta-analyses of DS (N = 180,866) and neuroticism (N = 170,910), performed by combining publicly available summary statistics from published studies with new genome-wide analyses of additional data. In these auxiliary analyses we identify two loci associated with DS and eleven with neuroticism, including two inversion polymorphisms. In depression data from an independent sample (N = 368,890), both DS associations replicate (p = 0.004 and p = 0.015).In our two joint analyses, we exploit the high genetic correlation between SWB, DS, and neuroticism (i) to evaluate the credibility of the 16 genome-wide significant associations across the three phenotypes, and (ii) to identify novel associations (beyond those identified by the GWAS). For (i), we investigate whether our three SWB-associated SNPs "quasi-replicate" by testing them for association with DS and neuroticism. We similarly examine the quasi-replication record of the DS and neuroticism loci by testing them for association with SWB. We find that the quasi-replication record closely matches what would be expected given our statistical power if none of the genome-wide significant associations were chance findings. These results strengthen the credibility of (most of) the original associations. For (ii), we u...

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Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

Cited by 292 publications

References 65 publications

Individual Differences in Personality Masculinity-Femininity: Examining the Effects of Genes, Environment, and Prenatal Hormone Transfer

Individual Differences in Personality Masculinity-Femininity: Examining the Effects of Genes, Environment, and Prenatal Hormone Transfer

Genetic and Environmental Stability of Neuroticism From Adolescence to Adulthood

Genetic Associations with Subjective Well-Being Also Implicate Depression and Neuroticism

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