Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Davies, Gail; Lam, Max; Harris, Sarah E.; Trampush, Joey W.; Luciano, Michelle; Hill, W. David; Hagenaars, Saskia P.; Ritchie, Stuart J.; Marioni, Riccardo E.; Fawns-Ritchie, Chloë; Liewald, David C.; Okely, Judith A.; Ahola‐Olli, Ari; Barnes, Catriona L. K.; Bertram, Lars; Bis, Joshua C.; Burdick, Katherine E.; Christoforou, Andrea; DeRosse, Pamela; Djurovic, Srdjan; Espeseth, Thomas; Giakoumaki, Stella G.; Giddaluru, Sudheer; Gustavson, Daniel E.; Hayward, Caroline; Hofer, Edith; Ikram, M. Arfan; Karlsson, Robert; Knowles, Emma; Lahti, Jari; Leber, Markus; Li, Shuo; Mather, Karen A.; Melle, Ingrid; Morris, Derek W.; Oldmeadow, Christopher; Palviainen, Teemu; Payton, Antony; Pazoki, Raha; Petrovic, Katja; Reynolds, Chandra A.; Sargurupremraj, Muralidharan; Scholz, Markus; Smith, Jennifer A.; Smith, Albert V.; Terzikhan, Natalie; Thalamuthu, Anbupalam; Trompet, Stella; Lee, Sven J. van der; Ware, Erin B.; Windham, B. Gwen; Wright, Margaret J.; Yang, Jingyun; Yu, Jian; Ames, David; Amin, Najaf; Amouyel, Philippe; Andreassen, Ole A.; Armstrong, Nicola J.; Assareh, Amelia A.; Attia, John; Attix, Deborah K.; Avramopoulos, Dimitrios; Bennett, David A.; Böhmer, Anne C.; Boyle, Patricia A.; Brodaty, Henry; Campbell, Harry; Cannon, Tyrone D.; Cirulli, Elizabeth T.; Congdon, Eliza; Conley, Emily Drabant; Corley, Janie; Cox, Simon R.; Dale, Anders M.; Dehghan, Abbas; Dick, Danielle M.; Dickinson, Dwight; Eriksson, Johan G.; Εvangelou, Εvangelos; Faul, Jessica D.; Ford, Ian; Freimer, Nelson A.; Gao, He; Giegling, Ina; Gillespie, Nathan A.; Gordon, Scott D.; Gottesman, Rebecca F.; Griswold, Michael; Gudnason, Vilmundur; Harris, Tamara B.; Hartmann, Annette M.; Hatzimanolis, Alex; Heiss, Gerardo; Holliday, Elizabeth G.; Joshi, Peter K.; Kähönen, Mika; Kardia, Sharon L.R.; Karlsson, Ida; Kleineidam, Luca; Knopman, David S.; Kochan, Nicole A.; Konte, Bettina; Kwok, John B.; Hellard, Stéphanie Le; Lee, Teresa; Lehtimäki, Terho; Li, Shu-Chen; Liu, Tian; Koini, Marisa; London, Edythe D.; Longstreth, W. T.; López, Oscar L.; Loukola, Anu; Luck, Tobias; Lundervold, Astri J.; Lundquist, Anders; Lyytikäinen, Leo-Pekka; Martin, Nicholas G.; Montgomery, Grant W.; Murray, Alison; Need, Anna C.; Noordam, Raymond; Nyberg, Lars; Ollier, William; Papenberg, Göran; Pattie, Alison; Polašek, Ozren; Poldrack, Russell A.; Psaty, Bruce M.; Reppermund, Simone; Riedel‐Heller, Steffi G.; Rose, Richard J.; Rotter, Jerome I.; Roussos, Panos; Rovio, Suvi; Saba, Yasaman; Sabb, Fred W.; Sachdev, Perminder S.; Satizabal, Claudia L.; Schmid, Matthias; Scott, Rodney J.; Scult, Matthew A.; Simino, Jeannette; Slagboom, P. Eline; Smyrnis, Nikolaos; Soumaré, Aïcha; Stefanis, Nikos C.; Stott, David J.; Straub, Richard E.; Sundet, Kjetil; Taylor, Adele M.; Taylor, Kent D.; Tzoulaki, Ioanna; Tzourio, Christophe; Uitterlinden, André G.; Vitart, Véronique; Voineskos, Aristotle N.; Kaprio, Jaakko; Wagner, Michael; Wagner, Holger; Weinhold, Leonie; Wen, Kexin; Widén, Elisabeth; Yang, Qiong; Zhao, Wei; Adams, Hieab H.H.; Arking, Dan E.; Bilder, Robert M.; Bitsios, Panos; Boerwinkle, Eric; Chiba‐Falek, Ornit; Corvin, Aiden; Jager, Philip L. De; Debette, Stéphanie; Donohoe, Gary; Elliott, Paul; Fitzpatrick, Annette L.; Gill, Michael; Glahn, David C.; Hägg, Sara; Hansell, Narelle K.; Hariri, Ahmad R.; Jukema, J. Wouter; Vuoksimaa, Eero; Keller, Matthew C.; Kremen, William S.; Launer, Lenore J.; Lindenberger, Ulman; Palotie, Aarno; Pedersen, Nancy L.; Pendleton, Neil; Porteous, David J.; Räikkönen, Katri; Raitakari, Olli T.; Ramı́rez, Alfredo; Reinvang, Ivar; Rudan, Igor; Rujescu, Dan; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R.; Starr, John M.; Steen, Vidar M.; Trollor, Julian N.; Turner, S.T.; Duijn, Cornelia M. van; Villringer, Arno; Weinberger, Daniel R.; Weir, David R.; Wilson, James F.; Malhotra, Anil K.; McIntosh, Andrew M.; Gale, Catharine R.; Seshadri, Sudha; Mosley, Thomas H.; Bressler, Jan; Lencz, Todd; Deary, Ian J.

doi:10.1038/s41467-018-04362-x

Cited by 577 publications

(612 citation statements)

References 87 publications

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“…Interestingly, the RBL2 locus has been associated with intelligence and cognitive function further strengthening its role in brain development . Our findings establish RBL2 as a candidate gene for an autosomal recessive neurodevelopmental disorder with intellectual disability, stereotypies and dysmorphic features adding variants with a monogenic effect to the allelic series.…”

Section: Discussionsupporting

confidence: 51%

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Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

Brunet

Radivojkov-Blagojevic

Lichtner

et al. 2020

Ann Clin Transl Neurol

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The RBL2 locus has been associated with intelligence and educational attainment but not with a monogenic disorder to date. RBL2 encodes p130, a member of the retinoblastoma protein family, which is involved in mediating neuron survival and death. Previous studies on p130 knockout mice revealing embryonic death and impaired neurogenesis underscore the importance of RBL2 in brain development. Exome sequencing in two siblings with severe intellectual disability, stereotypies and dysmorphic features identified biallelic loss‐of‐function variants c.556C>T, p.(Arg186Ter) and a deletion of exon 13–17 in RBL2 (NM_005611.3), establishing RBL2 as a candidate gene for an autosomal recessive neurodevelopmental disorder.

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Section: Discussionsupporting

confidence: 51%

“…Genome‐wide association studies (GWAS) have identified polymorphisms in the RBL2 locus to be associated with intelligence and educational attainment, but the gene has not been described in a monogenic context to date.…”

Section: Introductionmentioning

confidence: 99%

Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

Brunet

Radivojkov-Blagojevic

Lichtner

et al. 2020

Ann Clin Transl Neurol

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“…For genome‐wide significant findings from published GWAS of general cognitive function (Davies et al, ), cognitive performance (Lee et al, ), and intelligence (Savage et al, ), the observed fractions of same‐direction tests observed in our analyses of EA and AA participants were significantly greater than expected by chance (i.e., 50%). These results are displayed in Table .…”

Section: Resultssupporting

confidence: 41%

“…By comparison, in the COGENT study, polygenic risk analyses suggested correlations between cognitive performance and educational performance, whereas in our GNOVA analyses of the UK Biobank data, our results were correlated with other cognitive impairments in the general population and occupations associated with reduced educational attainment. Previous GNOVA analyses of the COGENT study results suggested correlations of the genomics of global cognition with SZ and BP (Davies et al, ).…”

Section: Discussionmentioning

confidence: 81%

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

Harvey

Sun

et al. 2019

American J of Med Genetics Pt B

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Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome‐wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome‐wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition‐related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

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“…As an additional analysis, we tested whether rs2526377 is connected to cognitive functioning before the clinical manifestations of AD so that the variant can be used as early marker of disease. To this end, we examined the association of rs2526377 with cognitive ability and educational attainment using the publicly available GWAS data (Davies et al, ; Okbay et al, ). The SNP minor allele (G) was positively associated with cognitive function ( p = .046; β = 0.011) and educational attainment ( p = .005; β = 0.01), which is consistent with the protective effect of the G allele for AD risk.…”

Section: Resultsmentioning

confidence: 99%

A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

Ghanbari

Munshi

et al. 2019

Human Mutation

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Noncoding RNAs have been widely recognized as essential mediators of gene regulation. However, in contrast to protein‐coding genes, much less is known about the influence of noncoding RNAs on human diseases. Here we examined the association of genetic variants located in primary microRNA sequences and long noncoding RNAs (lncRNAs) with Alzheimer disease (AD) by leveraging data from the largest genome‐wide association meta‐analysis of late‐onset AD. Variants annotated to 5 miRNAs and 10 lncRNAs (in seven distinct loci) exceeded the Bonferroni‐corrected significance threshold (p < 1.02 × 10−6). Among these, a leading variant (rs2526377:A>G) at the 17q22 locus annotated to two noncoding RNAs (MIR142 and BZRAP1‐AS) was significantly associated with a reduced risk of AD and fulfilled predefined criteria for being a functional variant. Our functional genomic analyses revealed that rs2526377 affects the promoter activity and decreases the expression of miR‐142. Moreover, differential expression analysis by RNA‐Seq in human iPSC‐derived neural progenitor cells and the hippocampus of miR‐142 knockout mice demonstrated multiple target genes of miR‐142 in the brain that are likely to be involved in the inflammatory and neurodegenerative manifestations of AD. These include TGFBR1 and PICALM, of which their derepression in the brain due to reduced expression levels of miR‐142‐3p may reduce the risk of AD.

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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Cited by 577 publications

References 87 publications

Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

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