Top

Published in:

Open Access 01-03-2022 | Original Article

Polygenic scores for handedness and their association with asymmetries in brain structure

Authors: Sebastian Ocklenburg, Dorothea Metzen, Caroline Schlüter, Christoph Fraenz, Larissa Arning, Fabian Streit, Onur Güntürkün, Robert Kumsta, Erhan Genç

Published in: Brain Structure and Function | Issue 2/2022

Abstract

Handedness is the most widely investigated motor preference in humans. The genetics of handedness and especially the link between genetic variation, brain structure, and right-left preference have not been investigated in detail. Recently, several well-powered genome-wide association studies (GWAS) on handedness have been published, significantly advancing the understanding of the genetic determinants of left and right-handedness. In the present study, we estimated polygenic scores (PGS) of handedness-based on the GWAS by de Kovel and Francks (Sci Rep 9: 5986, 2019) in an independent validation cohort (n = 296). PGS reflect the sum effect of trait-associated alleles across many genetic loci. For the first time, we could show that these GWAS-based PGS are significantly associated with individual handedness lateralization quotients in an independent validation cohort. Additionally, we investigated whether handedness-derived polygenic scores are associated with asymmetries in gray matter macrostructure across the whole brain determined using magnetic resonance imaging. None of these associations reached significance after correction for multiple comparisons. Our results implicate that PGS obtained from large-scale handedness GWAS are significantly associated with individual handedness in smaller validation samples with more detailed phenotypic assessment.

Available only for authorised users

Agerbo E, Trabjerg BB, Børglum AD, Schork AJ, Vilhjálmsson BJ, Pedersen CB, Hakulinen C, Albiñana C, Hougaard DM, Grove J, McGrath JJ, Bybjerg-Grauholm J, Mors O, Plana-Ripoll O, Werge T, Wray NR, Mortensen PB, Musliner KL (2021) Risk of early-onset depression associated with polygenic liability, parental psychiatric history, and socioeconomic status. JAMA Psychiat. https://doi.org/10.1001/jamapsychiatry.2020.4172CrossRef

Agnew-Blais JC, Belsky DW, Caspi A, Danese A, Moffitt TE, Polanczyk GV, Sugden K, Wertz J, Williams B, Lewis CM, Arseneault L (2021) Polygenic risk and the course of attention-deficit/hyperactivity disorder from childhood to young adulthood: findings from a nationally-representative cohort. J Am Acad Child Adolesc Psychiatr. https://doi.org/10.1016/j.jaac.2020.12.033CrossRef

Amunts K, Schlaug G, Schleicher A, Steinmetz H, Dabringhaus A, Roland PE, Zilles K (1996) Asymmetry in the human motor cortex and handedness. Neuroimage 4:216–222. https://doi.org/10.1006/nimg.1996.0073CrossRefPubMed

Amunts K, Jäncke L, Mohlberg H, Steinmetz H, Zilles K (2000) Interhemispheric asymmetry of the human motor cortex related to handedness and gender. Neuropsychologia 38:304–312. https://doi.org/10.1016/s0028-3932(99)00075-5CrossRefPubMed

Annett M (1996) In defence of the right shift theory. Percept Mot Skills 82:115–137. https://doi.org/10.2466/pms.1996.82.1.115CrossRefPubMed

Arning L, Ocklenburg S, Schulz S, Ness V, Gerding WM, Hengstler JG, Falkenstein M, Epplen JT, Güntürkün O, Beste C (2013) PCSK6 VNTR polymorphism is associated with degree of handedness but not direction of handedness. PLoS ONE 8:e67251. https://doi.org/10.1371/journal.pone.0067251CrossRefPubMedPubMedCentral

Brandler WM, Paracchini S (2014) The genetic relationship between handedness and neurodevelopmental disorders. Trends Mol Med 20:83–90. https://doi.org/10.1016/j.molmed.2013.10.008CrossRefPubMedPubMedCentral

Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, Timpson NJ, St Pourcain B, Smith GD, Ring SM, Stein J, Monaco AP, Talcott JB, Fisher SE, Webber C, Paracchini S (2013) Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genet. https://doi.org/10.1371/journal.pgen.1003751CrossRefPubMedPubMedCentral

Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7. https://doi.org/10.1186/s13742-015-0047-8CrossRefPubMedPubMedCentral

Choi SW, O’Reilly PF (2019) PRSice-2: polygenic risk score software for biobank-scale data. Gigascience. https://doi.org/10.1093/gigascience/giz082CrossRefPubMedPubMedCentral

Contestabile A, Colangiulo R, Lucchini M, Rouiller EM, Schmidlin E (2020) Variable interhemispheric asymmetry in layer v of the supplementary motor area following cervical hemisection in adult macaque monkeys. eNeuro. https://doi.org/10.1523/ENEURO.0280-20.2020CrossRefPubMedPubMedCentral

Crespi B, Read S, Hurd P (2018) The SETDB2 locus: evidence for a genetic link between handedness and atopic disease. Heredity (edinb) 120:77–82. https://doi.org/10.1038/s41437-017-0004-7CrossRef

Cuellar-Partida G, Tung JY, Eriksson N, Albrecht E, Aliev F, Andreassen OA, Barroso I, Beckmann JS, Boks MP, Boomsma DI, Boyd HA, Breteler MMB, Campbell H, Chasman DI, Cherkas LF, Davies G, de Geus EJC, Deary IJ, Deloukas P, Dick DM, Duffy DL, Eriksson JG, Esko T, Feenstra B, Geller F, Gieger C, Giegling I, Gordon SD, Han J, Hansen TF, Hartmann AM, Hayward C, Heikkilä K, Hicks AA, Hirschhorn JN, Hottenga J-J, Huffman JE, Hwang L-D, Ikram MA, Kaprio J, Kemp JP, Khaw K-T, Klopp N, Konte B, Kutalik Z, Lahti J, Li X, Loos RJF, Luciano M, Magnusson SH, Mangino M, Marques-Vidal P, Martin NG, McArdle WL, McCarthy MI, Medina-Gomez C, Melbye M, Melville SA, Metspalu A, Milani L, Mooser V, Nelis M, Nyholt DR, O’Connell KS, Ophoff RA, Palmer C, Palotie A, Palviainen T, Pare G, Paternoster L, Peltonen L, Penninx BWJH, Polasek O, Pramstaller PP, Prokopenko I, Raikkonen K, Ripatti S, Rivadeneira F, Rudan I, Rujescu D, Smit JH, Smith GD, Smoller JW, Soranzo N, Spector TD, Pourcain BS, Starr JM, Stefánsson H, Steinberg S, Teder-Laving M, Thorleifsson G, Stefánsson K, Timpson NJ, Uitterlinden AG, van Duijn CM, van Rooij FJA, Vink JM, Vollenweider P, Vuoksimaa E, Waeber G, Wareham NJ, Warrington N, Waterworth D, Werge T, Wichmann H-E, Widen E, Willemsen G, Wright AF, Wright MJ, Xu M, Zhao JH, Kraft P, Hinds DA, Lindgren CM, Mägi R, Neale BM, Evans DM, Medland SE (2020) Genome-wide association study identifies 48 common genetic variants associated with handedness. Nat Hum Behav. https://doi.org/10.1038/s41562-020-00956-yCrossRefPubMedPubMedCentral

Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis I Segmentation and Surface Reconstruction. Neuroimage 9:179–194. https://doi.org/10.1006/nimg.1998.0395CrossRefPubMed

de Kovel CGF, Francks C (2019) The molecular genetics of hand preference revisited. Sci Rep 9:5986. https://doi.org/10.1038/s41598-019-42515-0CrossRefPubMedPubMedCentral

de Kovel CGF, Carrión-Castillo A, Francks C (2019) A large-scale population study of early life factors influencing left-handedness. Sci Rep 9:584. https://doi.org/10.1038/s41598-018-37423-8CrossRefPubMedPubMedCentral

Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31:968–980. https://doi.org/10.1016/j.neuroimage.2006.01.021CrossRefPubMed

Dima D, Breen G (2015) Polygenic risk scores in imaging genetics: usefulness and applications. J Psychopharmacol 29:867–871. https://doi.org/10.1177/0269881115584470CrossRefPubMed

Engen MJ, Lyngstad SH, Ueland T, Simonsen CE, Vaskinn A, Smeland O, Bettella F, Lagerberg TV, Djurovic S, Andreassen OA, Melle I (2020) Polygenic scores for schizophrenia and general cognitive ability: associations with six cognitive domains, premorbid intelligence, and cognitive composite score in individuals with a psychotic disorder and in healthy controls. Transl Psychiatry 10:416. https://doi.org/10.1038/s41398-020-01094-9CrossRefPubMedPubMedCentral

Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 9:195–207. https://doi.org/10.1006/nimg.1998.0396CrossRefPubMed

Francks C, Maegawa S, Laurén J, Abrahams BS, Velayos-Baeza A, Medland SE, Colella S, Groszer M, McAuley EZ, Caffrey TM, Timmusk T, Pruunsild P, Koppel I, Lind PA, Matsumoto-Itaba N, Nicod J, Xiong L, Joober R, Enard W, Krinsky B, Nanba E, Richardson AJ, Riley BP, Martin NG, Strittmatter SM, Möller H-J, Rujescu D, St Clair D, Muglia P, Roos JL, Fisher SE, Wade-Martins R, Rouleau GA, Stein JF, Karayiorgou M, Geschwind DH, Ragoussis J, Kendler KS, Airaksinen MS, Oshimura M, DeLisi LE, Monaco AP (2007) LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Mol Psychiatr 12(1129–39):1057. https://doi.org/10.1038/sj.mp.4002053CrossRef

Guadalupe T, Willems RM, Zwiers MP, Arias Vasquez A, Hoogman M, Hagoort P, Fernandez G, Buitelaar J, Franke B, Fisher SE, Francks C (2014) Differences in cerebral cortical anatomy of left- and right-handers. Front Psychol 5:261. https://doi.org/10.3389/fpsyg.2014.00261CrossRefPubMedPubMedCentral

Güntürkün O, Ocklenburg S (2017) Ontogenesis of lateralization. Neuron 94:249–263. https://doi.org/10.1016/j.neuron.2017.02.045CrossRefPubMed

Güntürkün O, Ströckens F, Ocklenburg S (2020) Brain lateralization: a comparative perspective. Physiol Rev 100:1019–1063. https://doi.org/10.1152/physrev.00006.2019CrossRefPubMed

Hanakawa T, Parikh S, Bruno MK, Hallett M (2005) Finger and face representations in the ipsilateral precentral motor areas in humans. J Neurophysiol 93:2950–2958. https://doi.org/10.1152/jn.00784.2004CrossRefPubMed

Harada A, Teng J, Takei Y, Oguchi K, Hirokawa N (2002) MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction. J Cell Biol 158:541–549. https://doi.org/10.1083/jcb.200110134CrossRefPubMedPubMedCentral

Karolis VR, Corbetta M, Thiebaut de Schotten M (2019) The architecture of functional lateralisation and its relationship to callosal connectivity in the human brain. Nat Commun 10:1417. https://doi.org/10.1038/s41467-019-09344-1CrossRefPubMedPubMedCentral

Klöppel S, Vongerichten A, van Eimeren T, Frackowiak RSJ, Siebner HR (2007) Can left-handedness be switched? Insights from an early switch of handwriting. J Neurosci 27:7847–7853. https://doi.org/10.1523/JNEUROSCI.1299-07.2007CrossRefPubMedPubMedCentral

Knopik VS, Neiderhiser JM, DeFries JC, Plomin R (2017) Behavioral genetics: A primer. Worth, New York

Kompus K, Specht K, Ersland L, Juvodden HT, van Wageningen H, Hugdahl K, Westerhausen R (2012) A forced-attention dichotic listening fMRI study on 113 subjects. Brain Lang 121:240–247. https://doi.org/10.1016/j.bandl.2012.03.004CrossRefPubMed

Leach EL, Prefontaine G, Hurd PL, Crespi BJ (2014) The imprinted gene LRRTM1 mediates schizotypy and handedness in a nonclinical population. J Hum Genet 59:332–336. https://doi.org/10.1038/jhg.2014.30CrossRefPubMed

Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O, Zacher M, Nguyen-Viet TA, Bowers P, Sidorenko J, Karlsson Linnér R, Fontana MA, Kundu T, Lee C, Li H, Li R, Royer R, Timshel PN, Walters RK, Willoughby EA, Yengo L, Alver M, Bao Y, Clark DW, Day FR, Furlotte NA, Joshi PK, Kemper KE, Kleinman A, Langenberg C, Mägi R, Trampush JW, Verma SS, Wu Y, Lam M, Zhao JH, Zheng Z, Boardman JD, Campbell H, Freese J, Harris KM, Hayward C, Herd P, Kumari M, Lencz T, Luan J, Malhotra AK, Metspalu A, Milani L, Ong KK, Perry JRB, Porteous DJ, Ritchie MD, Smart MC, Smith BH, Tung JY, Wareham NJ, Wilson JF, Beauchamp JP, Conley DC, Esko T, Lehrer SF, Magnusson PKE, Oskarsson S, Pers TH, Robinson MR, Thom K, Watson C, Chabris CF, Meyer MN, Laibson DI, Yang J, Johannesson M, Koellinger PD, Turley P, Visscher PM, Benjamin DJ, Cesarini D (2018) Gene discovery and polygenic prediction from a genome wide association study of educational attainment in 1.1 million individuals. Nat Genet. https://doi.org/10.1038/s41588-018-0147-3CrossRefPubMedPubMedCentral

Lindell AK, Hudry K (2013) Atypicalities in cortical structure, handedness, and functional lateralization for language in autism spectrum disorders. Neuropsychol Rev 23:257–270. https://doi.org/10.1007/s11065-013-9234-5CrossRefPubMed

McManus IC (1991) The inheritance of left-handedness. Ciba Found Symp 162:251–267. https://doi.org/10.1002/9780470514160.ch15CrossRefPubMed

Medland SE, Duffy DL, Wright MJ, Geffen GM, Martin NG (2006) Handedness in twins: joint analysis of data from 35 samples. Twin Res Hum Genet 9:46–53. https://doi.org/10.1375/183242706776402885CrossRefPubMed

Medland SE, Duffy DL, Wright MJ, Geffen GM, Hay DA, Levy F, van Beijsterveldt CEM, Willemsen G, Townsend GC, White V, Hewitt AW, Mackey DA, Bailey JM, Slutske WS, Nyholt DR, Treloar SA, Martin NG, Boomsma DI (2009) Genetic influences on handedness: data from 25,732 Australian and Dutch twin families. Neuropsychologia 47(330):337. https://doi.org/10.1016/j.neuropsychologia.2008.09.005CrossRef

Mundorf A, Ocklenburg S (2021) Clinical neuroscience of lateralization. RoutledgeCrossRef

Ocklenburg S, Beste C, Güntürkün O (2013) Handedness: a neurogenetic shift of perspective. Neurosci Biobehav Rev 37:2788–2793. https://doi.org/10.1016/j.neubiorev.2013.09.014CrossRefPubMed

Ocklenburg S, Arning L, Gerding WM, Hengstler JG, Epplen JT, Güntürkün O, Beste C, Akkad DA (2016) Left-right axis differentiation and functional lateralization: a haplotype in the methyltransferase encoding gene SETDB2 might mediate handedness in healthy adults. Mol Neurobiol 53:6355–6361. https://doi.org/10.1007/s12035-015-9534-2CrossRefPubMed

Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113. https://doi.org/10.1016/0028-3932(71)90067-4CrossRefPubMed

Papadatou-Pastou M, Ntolka E, Schmitz J, Martin M, Munafò MR, Ocklenburg S, Paracchini S (2020) Human handedness: a meta-analysis. Psychol Bull 146:481–524. https://doi.org/10.1037/bul0000229CrossRefPubMed

Paracchini S, Diaz R, Stein J (2016) Advances in dyslexia genetics-new insights into the role of brain asymmetries. Adv Genet 96:53–97. https://doi.org/10.1016/bs.adgen.2016.08.003CrossRefPubMed

Persichetti AS, Avery JA, Huber L, Merriam EP, Martin A (2020) Layer-specific contributions to imagined and executed hand movements in human primary motor cortex. Curr Biol 30:1721-1725.e3. https://doi.org/10.1016/j.cub.2020.02.046CrossRefPubMedPubMedCentral

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795CrossRefPubMedPubMedCentral

Scerri TS, Brandler WM, Paracchini S, Morris AP, Ring SM, Richardson AJ, Talcott JB, Stein J, Monaco AP (2011) PCSK6 is associated with handedness in individuals with dyslexia. Hum Mol Genet 20:608–614. https://doi.org/10.1093/hmg/ddq475CrossRefPubMed

Schmitz J, Metz GAS, Güntürkün O, Ocklenburg S (2017) Beyond the genome-towards an epigenetic understanding of handedness ontogenesis. Prog Neurobiol 159:69–89. https://doi.org/10.1016/j.pneurobio.2017.10.005CrossRefPubMed

Sha Z, Schijven D, Carrion-Castillo A, Joliot M, Mazoyer B, Fisher SE, Crivello F, Francks C (2021) The genetic architecture of structural left-right asymmetry of the human brain. Nat Hum Behav. https://doi.org/10.1038/s41562-021-01069-w

Ströckens F, Güntürkün O, Ocklenburg S (2013) Limb preferences in non-human vertebrates. Laterality 18:536–575. https://doi.org/10.1080/1357650X.2012.723008CrossRefPubMed

Whalley HC, Hall L, Romaniuk L, Macdonald A, Lawrie SM, Sussmann JE, McIntosh AM (2015) Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk. Schizophr Res 161:484–489. https://doi.org/10.1016/j.schres.2014.10.046CrossRefPubMedPubMedCentral

Wiberg A, Ng M, Al Omran Y, Alfaro-Almagro F, McCarthy P, Marchini J, Bennett DL, Smith S, Douaud G, Furniss D (2019) Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics. Brain 142:2938–2947. https://doi.org/10.1093/brain/awz257CrossRefPubMedPubMedCentral

Wray NR, Lee SH, Mehta D, Vinkhuyzen AAE, Dudbridge F, Middeldorp CM (2014) Research review: polygenic methods and their application to psychiatric traits. J Child Psychol Psychiatr 55:1068–1087. https://doi.org/10.1111/jcpp.12295CrossRef

Yokoi A, Arbuckle SA, Diedrichsen J (2018) The Role of human primary motor cortex in the production of skilled finger sequences. J Neurosci 38:1430–1442. https://doi.org/10.1523/JNEUROSCI.2798-17.2017CrossRefPubMedPubMedCentral

Zach P, Vales K, Stuchlik A, Cermakova P, Mrzilkova J, Koutela A, Kutova M (2016) Effect of stress on structural brain asymmetry. Neuro Endocrinol Lett 37:253–264PubMed

Title: Polygenic scores for handedness and their association with asymmetries in brain structure
Authors: Sebastian Ocklenburg
Dorothea Metzen
Caroline Schlüter
Christoph Fraenz
Larissa Arning
Fabian Streit
Onur Güntürkün
Robert Kumsta
Erhan Genç
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 2/2022
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-021-02335-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Polygenic scores for handedness and their association with asymmetries in brain structure

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2022

A tale of two gradients: differences between the left and right hemispheres predict semantic cognition

Is it left or is it right? A classification approach for investigating hemispheric differences in low and high dimensionality

Hemispheric asymmetries in visual mental imagery

Asymmetry of brain structure and function: 40 years after Sperry’s Nobel Prize

Brain–behavior dynamics between the left fusiform and reading

Handedness and midsagittal corpus callosum morphology: a meta-analytic evaluation