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1.  Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder 
de Moor, Marleen H.M. | van den Berg, Stéphanie M. | Verweij, Karin J.H. | Krueger, Robert F. | Luciano, Michelle | Vasquez, Alejandro Arias | Matteson, Lindsay K. | Derringer, Jaime | Esko, Tõnu | Amin, Najaf | Gordon, Scott D. | Hansell, Narelle K. | Hart, Amy B. | Seppälä, Ilkka | Huffman, Jennifer E. | Konte, Bettina | Lahti, Jari | Lee, Minyoung | Miller, Mike | Nutile, Teresa | Tanaka, Toshiko | Teumer, Alexander | Viktorin, Alexander | Wedenoja, Juho | Abecasis, Goncalo 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 | de Wit, Harriet | Ding, Jun | Engelhardt, Barbara E. | Eriksson, Johan G. | Fedko, Iryna O. | Ferrucci, Luigi | Franke, Barbara | Giegling, Ina | Grucza, Richard | Hartmann, Annette M. | Heath, Andrew C. | Heinonen, Kati | Henders, Anjali K. | Homuth, Georg | Hottenga, Jouke-Jan | Janzing, Joost | 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 | Polasek, Ozren | Qian, Yong | Pulkki-Råback, Laura | Raitakari, Olli T. | Realo, Anu | Rose, Richard J. | Ruggiero, Daniela | Schmidt, Carsten O. | Slutske, Wendy S. | Sorice, Rossella | Starr, John M. | Pourcain, Beate St | Sutin, Angelina R. | Timpson, Nicholas J. | Trochet, Holly | Vermeulen, Sita | Vuoksimaa, Eero | Widen, Elisabeth | Wouda, Jasper | Wright, Margaret J. | Zgaga, Lina | Scotland, Generation | Porteous, David | 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. | van Duijn, Cornelia M. | Evans, David M. | Schlessinger, David | Pedersen, Nancy L. | Terracciano, Antonio | McGue, Matt | Penninx, Brenda W.J.H. | Martin, Nicholas G. | Boomsma, Dorret I.
JAMA psychiatry  2015;72(7):642-650.
Importance
Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases).
Objective
To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD.
Setting
30 cohorts with genome-wide genotype, personality and MDD data from the GPC.
Participants
The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia.
Main outcome measure(s)
Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status.
Results
A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts.
Conclusions and relevance
This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism, and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.
doi:10.1001/jamapsychiatry.2015.0554
PMCID: PMC4667957  PMID: 25993607
2.  Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium 
van den Berg, Stéphanie M. | de Moor, Marleen H. M. | Verweij, Karin J. H. | Krueger, Robert F. | Luciano, Michelle | Arias Vasquez, Alejandro | Matteson, Lindsay K. | Derringer, Jaime | Esko, Tõnu | Amin, Najaf | Gordon, Scott D. | Hansell, Narelle K. | Hart, Amy B. | Seppälä, Ilkka | Huffman, Jennifer E. | Konte, Bettina | Lahti, Jari | Lee, Minyoung | Miller, Mike | Nutile, Teresa | Tanaka, Toshiko | Teumer, Alexander | Viktorin, Alexander | Wedenoja, Juho | Abdellaoui, Abdel | Abecasis, Goncalo 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 | de Wit, Harriet | Ding, Jun | Engelhardt, Barbara E. | Eriksson, Johan G. | Fedko, Iryna O. | Ferrucci, Luigi | Franke, Barbara | Giegling, Ina | Grucza, Richard | Hartmann, Annette M. | Heath, Andrew C. | Heinonen, Kati | Henders, Anjali K. | Homuth, Georg | Hottenga, Jouke-Jan | Iacono, William G. | Janzing, Joost | 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 | Mbarek, Hamdi | Medland, Sarah E. | Mihailov, Evelin | Milaneschi, Yuri | Montgomery, Grant W. | Nauck, Matthias | Nivard, Michel G. | Ouwens, Klaasjan G. | Palotie, Aarno | Pettersson, Erik | Polasek, Ozren | Qian, Yong | Pulkki-Råback, Laura | Raitakari, Olli T. | Realo, Anu | Rose, Richard J. | Ruggiero, Daniela | Schmidt, Carsten O. | Slutske, Wendy S. | Sorice, Rossella | Starr, John M. | St Pourcain, Beate | Sutin, Angelina R. | Timpson, Nicholas J. | Trochet, Holly | Vermeulen, Sita | Vuoksimaa, Eero | Widen, Elisabeth | Wouda, Jasper | Wright, Margaret J. | Zgaga, Lina | Porteous, David | 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. | Penninx, Brenda W. J. H. | van Duijn, Cornelia M. | Evans, David M. | Schlessinger, David | Pedersen, Nancy L. | Terracciano, Antonio | McGue, Matt | Martin, Nicholas G. | Boomsma, Dorret I.
Behavior Genetics  2015;46:170-182.
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-015-9735-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10519-015-9735-5
PMCID: PMC4751159  PMID: 26362575
Personality; Phenotype harmonization; Common genetic variants; Imputation; Polygenic risk
4.  A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration 
de Vries, Paul S. | Chasman, Daniel I. | Sabater-Lleal, Maria | Chen, Ming-Huei | Huffman, Jennifer E. | Steri, Maristella | Tang, Weihong | Teumer, Alexander | Marioni, Riccardo E. | Grossmann, Vera | Hottenga, Jouke J. | Trompet, Stella | Müller-Nurasyid, Martina | Zhao, Jing Hua | Brody, Jennifer A. | Kleber, Marcus E. | Guo, Xiuqing | Wang, Jie Jin | Auer, Paul L. | Attia, John R. | Yanek, Lisa R. | Ahluwalia, Tarunveer S. | Lahti, Jari | Venturini, Cristina | Tanaka, Toshiko | Bielak, Lawrence F. | Joshi, Peter K. | Rocanin-Arjo, Ares | Kolcic, Ivana | Navarro, Pau | Rose, Lynda M. | Oldmeadow, Christopher | Riess, Helene | Mazur, Johanna | Basu, Saonli | Goel, Anuj | Yang, Qiong | Ghanbari, Mohsen | Willemsen, Gonneke | Rumley, Ann | Fiorillo, Edoardo | de Craen, Anton J. M. | Grotevendt, Anne | Scott, Robert | Taylor, Kent D. | Delgado, Graciela E. | Yao, Jie | Kifley, Annette | Kooperberg, Charles | Qayyum, Rehan | Lopez, Lorna M. | Berentzen, Tina L. | Räikkönen, Katri | Mangino, Massimo | Bandinelli, Stefania | Peyser, Patricia A. | Wild, Sarah | Trégouët, David-Alexandre | Wright, Alan F. | Marten, Jonathan | Zemunik, Tatijana | Morrison, Alanna C. | Sennblad, Bengt | Tofler, Geoffrey | de Maat, Moniek P. M. | de Geus, Eco J. C. | Lowe, Gordon D. | Zoledziewska, Magdalena | Sattar, Naveed | Binder, Harald | Völker, Uwe | Waldenberger, Melanie | Khaw, Kay-Tee | Mcknight, Barbara | Huang, Jie | Jenny, Nancy S. | Holliday, Elizabeth G. | Qi, Lihong | Mcevoy, Mark G. | Becker, Diane M. | Starr, John M. | Sarin, Antti-Pekka | Hysi, Pirro G. | Hernandez, Dena G. | Jhun, Min A. | Campbell, Harry | Hamsten, Anders | Rivadeneira, Fernando | Mcardle, Wendy L. | Slagboom, P. Eline | Zeller, Tanja | Koenig, Wolfgang | Psaty, Bruce M. | Haritunians, Talin | Liu, Jingmin | Palotie, Aarno | Uitterlinden, André G. | Stott, David J. | Hofman, Albert | Franco, Oscar H. | Polasek, Ozren | Rudan, Igor | Morange, Pierre-Emmanuel | Wilson, James F. | Kardia, Sharon L. R. | Ferrucci, Luigi | Spector, Tim D. | Eriksson, Johan G. | Hansen, Torben | Deary, Ian J. | Becker, Lewis C. | Scott, Rodney J. | Mitchell, Paul | März, Winfried | Wareham, Nick J. | Peters, Annette | Greinacher, Andreas | Wild, Philipp S. | Jukema, J. Wouter | Boomsma, Dorret I. | Hayward, Caroline | Cucca, Francesco | Tracy, Russell | Watkins, Hugh | Reiner, Alex P. | Folsom, Aaron R. | Ridker, Paul M. | O'Donnell, Christopher J. | Smith, Nicholas L. | Strachan, David P. | Dehghan, Abbas
Human Molecular Genetics  2015;25(2):358-370.
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
doi:10.1093/hmg/ddv454
PMCID: PMC4715256  PMID: 26561523
5.  Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits 
Pankratz, Nathan | Schick, Ursula M | Zhou, Yi | Zhou, Wei | Ahluwalia, Tarunveer Singh | Allende, Maria Laura | Auer, Paul L | Bork-Jensen, Jette | Brody, Jennifer A | Chen, Ming-Huei | Clavo, Vinna | Eicher, John D | Grarup, Niels | Hagedorn, Elliott J | Hu, Bella | Hunker, Kristina | Johnson, Andrew D | Leusink, Maarten | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Manichaikul, Ani | Marioni, Riccardo E | Nalls, Mike A | Pazoki, Raha | Smith, Albert Vernon | van Rooij, Frank J A | Yang, Min-Lee | Zhang, Xiaoling | Zhang, Yan | Asselbergs, Folkert W | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Cushman, Mary | de Bakker, Paul I W | Deary, Ian J | Dong, Liguang | Feitosa, Mary F | Floyd, James S | Franceschini, Nora | Franco, Oscar H | Garcia, Melissa E | Grove, Megan L | Gudnason, Vilmundur | Hansen, Torben | Harris, Tamara B | Hofman, Albert | Jackson, Rebecca D | Jia, Jia | Kähönen, Mika | Launer, Lenore J | Lehtimäki, Terho | Liewald, David C | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J F | Nguyen, Vy M | Numans, Mattijs E | Pedersen, Oluf | Psaty, Bruce M | Raitakari, Olli T | Rich, Stephen S | Rivadeneira, Fernando | Di Sant, Amanda M Rosa | Rotter, Jerome I | Starr, John M | Taylor, Kent D | Thuesen, Betina Heinsbæk | Tracy, Russell P | Uitterlinden, Andre G | Wang, Jiansong | Wang, Judy | Dehghan, Abbas | Huo, Yong | Cupples, L Adrienne | Wilson, James G | Proia, Richard L | Zon, Leonard I | O’Donnell, Christopher J | Reiner, Alex P | Ganesh, Santhi K
Nature genetics  2016;48(8):867-876.
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
doi:10.1038/ng.3607
PMCID: PMC5145000  PMID: 27399967
6.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
Background
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
Results
We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
Conclusion
We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1119-5
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
7.  The impact of genome-wide autozygosity on general cognitive ability 
Molecular psychiatry  2015;21(6):837-843.
Inbreeding depression refers to lower fitness among offspring of genetic relatives (1). This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents (2). Using dense genome-wide SNP data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4,854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row— to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 standard deviations among the offspring of first cousins (p = 0.003 - 0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome-wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships (3). These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
doi:10.1038/mp.2015.120
PMCID: PMC4803638  PMID: 26390830
8.  Intelligence and socioeconomic position in childhood in relation to frailty and cumulative allostatic load in later life: the Lothian Birth Cohort 1936 
Background
Information on childhood determinants of frailty or allostatic load in later life is sparse. We investigated whether lower intelligence and greater socioeconomic disadvantage in childhood increased the risk of frailty and higher allostatic load and explored the mediating roles of adult socioeconomic position, educational attainment and health behaviours.
Methods
Participants were 876 members of the Lothian Birth Cohort 1936 whose intelligence was assessed at age 11. At age 70, frailty was assessed using the Fried criteria. Measurements were made of fibrinogen, triglyceride, total and high-density lipoprotein cholesterol, albumin, glycated haemoglobin, C-reactive protein, BMI, and blood pressure from which an allostatic load score was calculated.
Results
In sex-adjusted analyses, lower intelligence and lower social class in childhood were associated with an increased risk of frailty: relative risks (95% confidence intervals) were 1.57 (1.21, 2.03) for a standard deviation decrease in intelligence and 1.48 (1.12, 1.96) for a category decrease in social class. In the fully-adjusted model, both associations ceased to be significant: relative risks were 1.13 (0.83, 1.54) and 1.19 (0.86, 1.61) respectively. Educational attainment had a significant mediating effect. Lower childhood intelligence in childhood, but not social class, was associated with higher allostatic load. The sex-adjusted coefficient for allostatic load for a standard deviation decrease in intelligence was 0.10 (0.07, 0.14). In the fully-adjusted model, this association was attenuated but remained significant (0.05 (0.01, 0.09)).
Conclusion
Further research will need to investigate the mechanisms whereby lower childhood intelligence is linked to higher allostatic load in later life.
doi:10.1136/jech-2015-205789
PMCID: PMC4820036  PMID: 26700299
frailty; intelligence; socioeconomic position; childhood; allostatic load
9.  Personality and Other Lifelong Influences on Older‐Age Health and Wellbeing: Preliminary Findings in Two Scottish Samples 
European Journal of Personality  2016;30(5):438-455.
Abstract
Recent observations that personality traits are related to later‐life health and wellbeing have inspired considerable interest in exploring the mechanisms involved. Other factors, such as cognitive ability and education, also show longitudinal influences on health and wellbeing, but it is not yet clear how all these early‐life factors together contribute to later‐life health and wellbeing. In this preliminary study, we assessed hypothesised relations among these variables across the life course, using structural equation modelling in a sample assessed on dependability (a personality trait related to conscientiousness) in childhood, cognitive ability and social class in childhood and older age, education, and health and subjective wellbeing in older age. Our models indicated that both health and subjective wellbeing in older age were influenced by childhood IQ and social class, via education. Some older‐age personality traits mediated the effects of early‐life variables, on subjective wellbeing in particular, but childhood dependability did not show significant associations. Our results therefore did not provide evidence that childhood dependability promotes older‐age health and wellbeing, but did highlight the importance of other early‐life factors, particularly characteristics that contribute to educational attainment. Further, personality in later life may mediate the effects of early‐life factors on health and subjective wellbeing. © 2016 The Authors. European Journal of Personality published by John Wiley & Sons Ltd on behalf of European Association of Personality Psychology
doi:10.1002/per.2068
PMCID: PMC5111597  PMID: 27867259
personality; cognitive ability; education; health; subjective wellbeing; longitudinal study
10.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M L | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G | Fontana, Mark Alan | Meddens, S Fleur W | Linnér, Richard Karlsson | Rietveld, Cornelius A | Derringer, Jaime | Gratten, Jacob | Lee, James J | Liu, Jimmy Z | de Vlaming, Ronald | Ahluwalia, Tarunveer S | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C | Davies, Gail | Furlotte, Nicholas A | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J | Miller, Michael B | Lind, Penelope A | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Minica, Camelia C | Nolte, Ilja M | Mook-Kanamori, Dennis O | van der Most, Peter J | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Thorleifsson, Gudmar | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Bergmann, Sven | Bjornsdottir, Gyda | Boyle, Patricia A | Cherney, Samantha | Cox, Simon R | Davis, Oliver S P | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T | Fatemifar, Ghazaleh | Faul, Jessica D | Ferrucci, Luigi | Forstner, Andreas J | Gieger, Christian | Gupta, Richa | Harris, Tamara B | Harris, Juliette M | Holliday, Elizabeth G | Hottenga, Jouke-Jan | De Jager, Philip L | Kaakinen, Marika A | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J | Franke, Lude | Li-Gao, Ruifang | Liewald, David C | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W | Mosing, Miriam A | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J | Smith, Jennifer A | Sutin, Angelina R | Trzaskowski, Maciej | Vinkhuyzen, Anna E | Yu, Lei | Zabaneh, Delilah | Attia, John R | Bennett, David A | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J | van Duijn, Cornelia M | Eriksson, Johan G | Bültmann, Ute | de Geus, Eco J C | Groenen, Patrick J F | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A | Haworth, Claire M A | Hayward, Caroline | Heath, Andrew C | Hinds, David A | Hyppönen, Elina | Iacono, William G | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L R | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D | Lehtimäki, Terho | Magnusson, Patrik K E | Martin, Nicholas G | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J | Pasterkamp, Gerard | Pedersen, Nancy L | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S | Rosendaal, Frits R | den Ruijter, Hester M | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z | Sørensen, Thorkild I A | Spector, Tim D | Starr, John M | Stefansson, Kari | Steptoe, Andrew | Terracciano, Antonio | Thorsteinsdottir, Unnur | Thurik, A Roy | Timpson, Nicholas J | Tiemeier, Henning | Uitterlinden, André G | Vollenweider, Peter | Wagner, Gert G | Weir, David R | Yang, Jian | Conley, Dalton C | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I | Medland, Sarah E | Meyer, Michelle N | Pickrell, Joseph K | Esko, Tõnu | Krueger, Robert F | Beauchamp, Jonathan P | Koellinger, Philipp D | Benjamin, Daniel J | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) 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.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
11.  Examining if being overweight really confers protection against dementia: Sixty-four year follow-up of participants in the Glasgow University alumni cohort study 
Background
Recent large-scale studies suggest that obesity and overweight may confer protection against future dementia. This observation could, however, be generated by reverse causality. That is, weight loss in the incipient phase of dementia ascribed to diminished self-care, including sub-optimal nutrition, would have the effect of generating such an inverse association. One approach to circumventing this problem would be to measure weight in a population which is young enough to be free of the symptoms of dementia which is then followed up for dementia occurrence over many decades.
Methods
In a prospective cohort study, body mass index, and other potential risk factors, were measured in 9547 male university undergraduates (mean age 20.5 years) in 1948–68 who were then linked to national mortality registers.
Results
Of 2537 deaths over a mean of 50.6 years follow up, 140 were ascribed to dementia. There was no association between overweight and future dementia deaths (age-adjusted hazard ratio; 95 % confidence interval: 0.93; 0.49, 1.79).
Conclusion
In this cohort study of former university students, being overweight in youth did not confer protection against later dementia death.
doi:10.1186/s12952-016-0062-z
PMCID: PMC5090948  PMID: 27802801
Cohort; Dementia; Epidemiology; Life course; Obesity; Overweight; Risk factors
12.  Predictors of ageing-related decline across multiple cognitive functions 
Intelligence  2016;59:115-126.
It is critical to discover why some people's cognitive abilities age better than others'. We applied multivariate growth curve models to data from a narrow-age cohort measured on a multi-domain IQ measure at age 11 years and a comprehensive battery of thirteen measures of visuospatial, memory, crystallized, and processing speed abilities at ages 70, 73, and 76 years (n = 1091 at age 70). We found that 48% of the variance in change in performance on the thirteen cognitive measures was shared across all measures, an additional 26% was specific to the four ability domains, and 26% was test-specific. We tested the association of a wide variety of sociodemographic, fitness, health, and genetic variables with each of these cognitive change factors. Models that simultaneously included all covariates accounted for appreciable proportions of variance in the cognitive change factors (e.g. approximately one third of the variance in general cognitive change). However, beyond physical fitness and possession of the APOE e4 allele, very few predictors were incrementally associated with cognitive change at statistically significant levels. The results highlight a small number of factors that predict differences in cognitive ageing, and underscore that correlates of cognitive level are not necessarily predictors of decline. Even larger samples will likely be required to identify additional variables with more modest associations with normal-range heterogeneity in aging-related cognitive declines.
Highlights
•We modeled aging-related cognitive decline from age 70 to 76 in a narrow-age sample.•A general factor explained 48% of variance in cognitive change.•Of numerous covariates, few significant predictors of change emerged.•Cognitive ageing is likely a process with few large-effect predictors.
doi:10.1016/j.intell.2016.08.007
PMCID: PMC5127886  PMID: 27932854
Cognitive ageing; Cognitive decline; Longitudinal; Structural equation modeling
13.  Associations between education and brain structure at age 73 years, adjusted for age 11 IQ 
Neurology  2016;87(17):1820-1826.
Objective:
To investigate how associations between education and brain structure in older age were affected by adjusting for IQ measured at age 11.
Methods:
We analyzed years of full-time education and measures from an MRI brain scan at age 73 in 617 community-dwelling adults born in 1936. In addition to average and vertex-wise cortical thickness, we measured total brain atrophy and white matter tract fractional anisotropy. Associations between brain structure and education were tested, covarying for sex and vascular health; a second model also covaried for age 11 IQ.
Results:
The significant relationship between education and average cortical thickness (β = 0.124, p = 0.004) was reduced by 23% when age 11 IQ was included (β = 0.096, p = 0.041). Initial associations between longer education and greater vertex-wise cortical thickness were significant in bilateral temporal, medial-frontal, parietal, sensory, and motor cortices. Accounting for childhood intelligence reduced the number of significant vertices by >90%; only bilateral anterior temporal associations remained. Neither education nor age 11 IQ was significantly associated with total brain atrophy or tract-averaged fractional anisotropy.
Conclusions:
The association between years of education and brain structure ≈60 years later was restricted to cortical thickness in this sample; however, the previously reported associations between longer education and a thicker cortex are likely to be overestimates in terms of both magnitude and distribution. This finding has implications for understanding, and possibly ameliorating, life-course brain health.
doi:10.1212/WNL.0000000000003247
PMCID: PMC5089529  PMID: 27664981
14.  Physical, social, psychological and existential trajectories of loss and adaptation towards the end of life for older people living with frailty: a serial interview study 
BMC Geriatrics  2016;16:176.
Background
The experiences of people with cancer and organ disease have been described across different dimensions of need as they approach death. Such information is lacking for frail older people approaching death, but could highlight how a palliative approach might be relevant for this population.
Methods
Cognitively intact, community dwelling adults considered to be moderately or severely frail were recruited from a medical day hospital. Those recruited nominated an informal carer and case-linked professional. Qualitative in-depth serial interviews with older people and their informal carers were conducted over an 18 month period, and single interviews with case-linked healthcare professionals. Interviews were recorded, transcribed and narrative analytical techniques were used to compile case studies.
Results
Thirty-four participants (13 patients, 13 informal carers and 8 healthcare professionals) completed 40 individual, 14 joint and 8 professional interviews. Five patients died during the study. The analysis highlighted a dynamic balance between losses and adaptations. Three typical patterns of multi-dimensional change emerged. 1) Maintenance of psychological and existential well-being with a gradual social decline mirroring the physical deterioration. 2) a gradual reduction in both psychological and existential well-being. 3) a marked downturn in social, psychological and existential well-being before death. Frail older people sustained their well-being through maintaining a sense-of-self, garnering support from carers and community structures, and focusing on living from day to day. Their well-being lessened when they lost their sense-of-self, feeling alienated from the world, and confused over the cause of their circumstances. Death remained distant and ‘undiagnosed’. Social and community frameworks were essential for supporting their well-being.
Conclusions
Multidimensional end-of-life trajectories for frail older people differed from those with other conditions. Alleviating psychological, social and existential distress should be a priority of care as frail older people reach the end of life. The current palliative care model is problematic for this group. Care should address future concerns and not necessarily involve a focus on death or place of death.
doi:10.1186/s12877-016-0350-y
PMCID: PMC5072327  PMID: 27765011
Palliative care; Qualitative research; Older persons; Frailty; Functional decline
15.  Environmental risk factors for dementia: a systematic review 
BMC Geriatrics  2016;16:175.
Background
Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementia have been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia.
Methods
We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of review articles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed.
Results
We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields.
Conclusions
Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations.
doi:10.1186/s12877-016-0342-y
PMCID: PMC5059894  PMID: 27729011
Dementia; Alzheimer’s disease; Environment; Epidemiology; Risk factors
16.  Bilingualism, social cognition and executive functions: A tale of chickens and eggs 
Neuropsychologia  2016;91:299-306.
The influence of bilingualism on cognitive functioning is currently a topic of intense scientific debate. The strongest evidence for a cognitive benefit of bilingualism has been demonstrated in executive functions. However, the causal direction of the relationship remains unclear: does learning other languages improve executive functions or are people with better executive abilities more likely to become bilingual?
To address this, we examined 90 male participants of the Lothian Birth Cohort 1936; 26 were bilingual, 64 monolingual. All participants underwent an intelligence test at age 11 years and were assessed on a wide range of executive and social cognition tasks at age 74. The only notable differences between both groups were found for the Simon Effect (which indexes stimulus-response conflict resolution; β=−.518, p=0.025) and a trend effect for the Faux Pas task (a measure of complex theory of mind; ToM, β=0.432, p=0.060). Controlling for the influence of childhood intelligence, parental and own social class significantly attenuated the bilingual advantage on the Faux Pas test (β=0.058, p=0.816), whereas the Simon task advantage remained (β=−.589, p=0.049).
We find some weak evidence that the relationship between bilingualism and cognitive functions may be selective and bi-directional. Pre-existing cognitive and social class differences from childhood may influence both ToM ability in older age and the likelihood of learning another language; yet, bilingualism does not appear to independently contribute to Faux Pas score. Conversely, learning a second language is related to better conflict processing, irrespective of initial childhood ability or social class.
Highlights
•We assessed executive functions and social cognition in 90 men aged 74 years.•We found no difference between bilinguals and monolinguals on the majority of tests.•Bilinguals scored higher than monolinguals on the Faux Pas task and Simon Task.•Differences on the Faux Pas task were attenuated by age 11 IQ and social class.•Bilingual advantage on the Simon Task was independent of age 11 IQ and social class.
doi:10.1016/j.neuropsychologia.2016.08.029
PMCID: PMC5090873  PMID: 27586077
Bilingualism; Executive functions; Social cognition; Childhood intelligence
17.  GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium 
Aging Cell  2016;15(5):792-800.
Summary
Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
doi:10.1111/acel.12468
PMCID: PMC5013019  PMID: 27325353
aging; genomewide association; meta‐analysis; muscle strength; older adults; SNP
18.  GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium 
Aging Cell  2016;15(5):792-800.
Summary
Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
doi:10.1111/acel.12468
PMCID: PMC5013019  PMID: 27325353
aging; genomewide association; meta‐analysis; muscle strength; older adults; SNP
19.  Associations among height, body mass index and intelligence from age 11 to age 78 years 
BMC Geriatrics  2016;16:167.
Background
Intelligence is related to both height and body mass index (BMI) at various stages of life. Several studies have demonstrated longitudinal relationships between these measures, but none has established whether height and intelligence, or BMI and intelligence are linked from childhood through to older age.
Methods
We assessed the relations between these measures over an interval of up to 67 years using data from the 36-Day Sample, an initially-representative sample of Scottish people born in 1936, assessed at age 11 years (N = 6,291) and again at 77–78 years (N = 722). This paper focuses on the 423 participants (6.7 % of the original sample) who provided relevant data in late adulthood.
Results
Height and intelligence were significantly positively associated in childhood (β = .23) and late adulthood (β = .21–.29). Longitudinal correlations also showed that childhood intelligence predicted late-adulthood height (β = .20), and childhood height predicted late-adulthood cognitive ability (β = .12–.14). We observed no significant relationship between BMI and intelligence either in childhood or in late adulthood, nor any longitudinal association between the two in this sample.
Conclusions
Our results on height and intelligence are the first to demonstrate that their relationship spans almost seven decades, from childhood through to late adulthood, and they call for further investigation into the mechanisms underlying this lifelong association.
Electronic supplementary material
The online version of this article (doi:10.1186/s12877-016-0340-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12877-016-0340-0
PMCID: PMC5041406  PMID: 27681526
Intelligence; Height; Body mass index; Ageing; Longitudinal study; 36-day sample
20.  APOE/TOMM 40 genetic loci, white matter hyperintensities, and cerebral microbleeds 
International Journal of Stroke  2015;10(8):1297-1300.
Background
Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease.
Aim and/or hypothesis
To test for independent associations between two Alzheimer's disease‐susceptibility gene loci – APOE ε and the TOMM 40 ‘523’ poly‐T repeat – and white matter hyperintensities/cerebral microbleed burden in community‐dwelling older adults.
Methods
Participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε and TOMM 40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74).
Results
No significant effects of APOE ε or TOMM 40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants.
Conclusions
Lack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature.
doi:10.1111/ijs.12615
PMCID: PMC4950052  PMID: 26310205
brain microbleeds; epidemiology; MRI; neurology; risk factors; vascular events
21.  Independent Evidence for an Association between General Cognitive Ability and a Genetic Locus for Educational Attainment 
Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genomewide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability (“g”) in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47×10−4) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94×10−7), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65×10−9). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.
doi:10.1002/ajmg.b.32319
PMCID: PMC4500051  PMID: 25951819
neurocognition; general cognitive ability; educational attainment; genetics; GWAS; proxy phenotype
22.  Intelligence and socioeconomic position in childhood in relation to frailty and cumulative allostatic load in later life: the Lothian Birth Cohort 1936 
Background
Information on childhood determinants of frailty or allostatic load in later life is sparse. We investigated whether lower intelligence and greater socioeconomic disadvantage in childhood increased the risk of frailty and higher allostatic load, and explored the mediating roles of adult socioeconomic position, educational attainment and health behaviours.
Methods
Participants were 876 members of the Lothian Birth Cohort 1936 whose intelligence was assessed at age 11. At age 70, frailty was assessed using the Fried criteria. Measurements were made of fibrinogen, triglyceride, total and high-density lipoprotein cholesterol, albumin, glycated haemoglobin, C reactive protein, body mass index and blood pressure, from which an allostatic load score was calculated.
Results
In sex-adjusted analyses, lower intelligence and lower social class in childhood were associated with an increased risk of frailty: relative risks (95% CIs) were 1.57 (1.21 to 2.03) for a SD decrease in intelligence and 1.48 (1.12 to 1.96) for a category decrease in social class. In the fully adjusted model, both associations ceased to be significant: relative risks were 1.13 (0.83 to 1.54) and 1.19 (0.86 to 1.61), respectively. Educational attainment had a significant mediating effect. Lower childhood intelligence in childhood, but not social class, was associated with higher allostatic load. The sex-adjusted coefficient for allostatic load for a SD decrease in intelligence was 0.10 (0.07 to 0.14). In the fully adjusted model, this association was attenuated but remained significant (0.05 (0.01 to 0.09)).
Conclusions
Further research will need to investigate the mechanisms whereby lower childhood intelligence is linked to higher allostatic load in later life.
doi:10.1136/jech-2015-205789
PMCID: PMC4820036  PMID: 26700299
COGNITION; ELDERLY; SOCIAL CLASS; Cohort studies
23.  Vascular risk factors and progression of white matter hyperintensities in the Lothian Birth Cohort 1936 
Neurobiology of Aging  2016;42:116-123.
We aimed to determine associations between multiple vascular risk factors (VRF) at ∼73 years and progression of white matter hyperintensities (WMH) from ∼73 years to ∼76 years. We calculated correlations and generalized estimating equation models of a comprehensive range of VRF at 73 years and change in WMH volume from 73 years to 76 years. Higher systolic (rho = 0.126, p = 0.009) and diastolic (rho = 0.120, p = 0.013) blood pressure at 73 years were significant predictors for greater WMH volume at 76 years in a simple correlation model. However, neither measured blood pressure nor self-reported hypertension at 73 years was significant predictors of WMH volume change in a fully adjusted model which accounted for initial WMH volume at 73 years. Lower high-density lipoprotein cholesterol (beta = −0.15 % intracranial, −1.80 mL; p < 0.05) and current smoking (beta = 0.43 % intracranial, 5.49 mL; p < 0.05) were the only significant VRF predictors of WMH volume change from 73 years to 76 years. A focus on smoking cessation and lipid lowering, not just antihypertensives, may lead to a reduction in WMH growth in the eighth decade of life.
Graphical abstract
doi:10.1016/j.neurobiolaging.2016.03.011
PMCID: PMC4869590  PMID: 27143428
White matter damage; White matter hyperintensities; Vascular risk factors; Aging; MRI
24.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
BACKGROUND
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
doi:10.1016/j.biopsych.2014.08.027
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
25.  Brain volumetric changes and cognitive ageing during the eighth decade of life 
Human Brain Mapping  2015;36(12):4910-4925.
Abstract
Later‐life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing‐related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow‐age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow‐up). We used latent variable modeling to extract error‐free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r‐values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life. Hum Brain Mapp 36:4910–4925, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc
doi:10.1002/hbm.22959
PMCID: PMC4832269  PMID: 26769551
brain volume; structural MRI; age‐related cognitive decline; longitudinal study; white matter hyperintensities

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