Advertisement

Impact of Polygenic Risk for Schizophrenia on Cortical Structure in UK Biobank

      Abstract

      Background

      Schizophrenia is a neurodevelopmental disorder with many genetic variants of individually small effect contributing to phenotypic variation. Lower cortical thickness (CT), surface area, and cortical volume have been demonstrated in people with schizophrenia. Furthermore, a range of obstetric complications (e.g., lower birth weight) are consistently associated with an increased risk for schizophrenia. We investigated whether a high polygenic risk score for schizophrenia (PGRS-SCZ) is associated with CT, surface area, and cortical volume in UK Biobank, a population-based sample, and tested for interactions with birth weight.

      Methods

      Data were available for 2864 participants (nmale/nfemale = 1382/1482; mean age = 62.35 years, SD = 7.40). Linear mixed models were used to test for associations among PGRS-SCZ and cortical volume, surface area, and CT and between PGRS-SCZ and birth weight. Interaction effects of these variables on cortical structure were also tested.

      Results

      We found a significant negative association between PGRS-SCZ and global CT; a higher PGRS-SCZ was associated with lower CT across the whole brain. We also report a significant negative association between PGRS-SCZ and insular lobe CT. PGRS-SCZ was not associated with birth weight and no PGRS-SCZ × birth weight interactions were found.

      Conclusions

      These results suggest that individual differences in CT are partly influenced by genetic variants and are most likely not due to factors downstream of disease onset. This approach may help to elucidate the genetic pathophysiology of schizophrenia. Further investigation in case-control and high-risk samples could help identify any localized effects of PGRS-SCZ, and other potential schizophrenia risk factors, on CT as symptoms develop.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Matheson S.L.
        • Shepherd A.M.
        • Laurens K.R.
        • Carr V.J.
        A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia.
        Schizophr Res. 2011; 133: 133-142
        • Gejman P.V.
        • Sanders A.R.
        • Duan J.
        The role of genetics in the etiology of schizophrenia.
        Psychiatr Clin North Am. 2010; 33: 35-66
        • Purcell S.M.
        • Wray N.R.
        • Stone J.L.
        • Visscher P.M.
        • O'Donovan M.C.
        • Sullivan P.F.
        • et al.
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752
        • Lee S.H.
        • DeCandia T.R.
        • Ripke S.
        • Yang J.
        • Sullivan P.F.
        • Goddard M.E.
        • et al.
        Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs.
        Nat Genet. 2012; 44: 247-250
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Ripke S.
        • O'Dushlaine C.
        • Chambert K.
        • Moran J.L.
        • Kähler A.K.
        • Akterin S.
        • et al.
        Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
        Nat Genet. 2013; 45: 1150-1159
        • Kinros J.
        • Reichenberg A.
        • Frangou S.
        The neurodevelopmental theory of schizophrenia: Evidence from studies of early onset cases.
        Isr J Psychiatry Relat Sci. 2010; 47: 110-117
        • Rapoport J.L.
        • Addington A.M.
        • Frangou S.
        • Psych M.R.
        The neurodevelopmental model of schizophrenia: Update 2005.
        Mol Psychiatry. 2005; 10: 434-449
        • Rapoport J.L.
        • Addington A.
        • Frangou S.
        The neurodevelopmental model of schizophrenia: What can very early onset cases tell us?.
        Curr Psychiatry Rep. 2005; 7: 81-82
        • Kong L.
        • Herold C.J.
        • Zöllner F.
        • Salat D.H.
        • Lässer M.M.
        • Schmid L.A.
        • et al.
        Comparison of grey matter volume and thickness for analysing cortical changes in chronic schizophrenia: A matter of surface area, grey/white matter intensity contrast, and curvature.
        Psychiatry Res. 2015; 231: 176-183
        • Wierenga L.M.
        • Langen M.
        • Oranje B.
        • Durston S.
        Unique developmental trajectories of cortical thickness and surface area.
        Neuroimage. 2014; 87: 120-126
        • Peper J.S.
        • Brouwer R.M.
        • Boomsma D.I.
        • Kahn R.S.
        • Hulshoff Pol H.E.
        Genetic influences on human brain structure: A review of brain imaging studies in twins.
        Hum Brain Mapp. 2007; 28: 464-473
        • Kremen W.S.
        • Prom-Wormley E.
        • Panizzon M.S.
        • Eyler L.T.
        • Fischl B.
        • Neale M.C.
        • et al.
        Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study.
        Neuroimage. 2010; 49: 1213-1223
        • Wright I.C.
        • Sham P.
        • Murray R.M.
        • Weinberger D.R.
        • Bullmore E.T.
        Genetic contributions to regional variability in human brain structure: Methods and preliminary results.
        Neuroimage. 2002; 17: 256-271
        • Panizzon M.S.
        • Fennema-Notestine C.
        • Eyler L.T.
        • Jernigan T.L.
        • Prom-Wormley E.
        • Neale M.
        • et al.
        Distinct genetic influences on cortical surface area and cortical thickness.
        Cereb Cortex. 2009; 19: 2728-2735
        • Ellison-Wright I.
        • Bullmore E.
        Anatomy of bipolar disorder and schizophrenia: A meta-analysis.
        Schizophr Res. 2010; 117: 1-12
        • Gupta C.N.
        • Calhoun V.D.
        • Rachakonda S.
        • Chen J.
        • Patel V.
        • Liu J.
        • et al.
        Patterns of gray matter abnormalities in schizophrenia based on an international mega-analysis.
        Schizophr Bull. 2015; 41: 1133-1142
        • Rimol L.M.
        • Nesvåg R.
        • Hagler D.J.
        • Bergmann O.
        • Fennema-Notestine C.
        • Hartberg C.B.
        • et al.
        Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder.
        Biol Psychiatry. 2012; 71: 552-560
        • Goldman A.L.
        • Pezawas L.
        • Mattay V.S.
        • Fischl B.
        • Verchinski B.A.
        • Zoltick B.
        • et al.
        Heritability of brain morphology related to schizophrenia: A large-scale automated magnetic resonance imaging segmentation study.
        Biol Psychiatry. 2008; 63: 475-483
        • Honea R.A.
        • Meyer-Lindenberg A.
        • Hobbs K.B.
        • Pezawas L.
        • Mattay V.S.
        • Egan M.F.
        • et al.
        Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings.
        Biol Psychiatry. 2008; 63: 465-474
        • Goghari V.M.
        • Rehm K.
        • Carter C.S.
        • MacDonald A.W.
        Regionally specific cortical thinning and gray matter abnormalities in the healthy relatives of schizophrenia patients.
        Cereb Cortex. 2007; 17: 415-424
        • Honea R.
        • Crow T.J.
        • Passingham D.
        • Mackay C.E.
        Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies.
        Am J Psychiatry. 2005; 162: 2233-2245
        • Olabi B.
        • Ellison-Wright I.
        • McIntosh A.M.
        • Wood S.J.
        • Bullmore E.
        • Lawrie S.M.
        Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies.
        Biol Psychiatry. 2011; 70: 88-96
        • Gutiérrez-Galve L.
        • Wheeler-Kingshott C.A.
        • Altmann D.R.
        • Price G.
        • Chu E.M.
        • Leeson V.C.
        • et al.
        Changes in the frontotemporal cortex and cognitive correlates in first-episode psychosis.
        Biol Psychiatry. 2010; 68: 51-60
        • Brans R.G.
        • van Haren N.E.
        • van Baal G.C.
        • Schnack H.G.
        • Kahn R.S.
        • Hulshoff Pol H.E.
        Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
        Arch Gen Psychiatry. 2008; 65: 1259-1268
        • Boos H.B.
        • Aleman A.
        • Cahn W.
        • Hulshoff Pol H.
        • Kahn R.S.
        Brain volumes in relatives of patients with schizophrenia: A meta-analysis.
        Arch Gen Psychiatry. 2007; 64: 297-304
        • Cannon T.D.
        • van Erp T.G.
        • Rosso I.M.
        • Huttunen M.
        • Lönnqvist J.
        • Pirkola T.
        • et al.
        Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls.
        Arch Gen Psychiatry. 2002; 59: 35-41
        • Jalbrzikowski M.
        • Jonas R.
        • Senturk D.
        • Patel A.
        • Chow C.
        • Green M.F.
        • et al.
        Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms.
        Neuroimage Clin. 2013; 3: 405-415
        • van Haren N.E.
        • Schnack H.G.
        • Cahn W.
        • van den Heuvel M.P.
        • Lepage C.
        • Collins L.
        • et al.
        Changes in cortical thickness during the course of illness in schizophrenia.
        Arch Gen Psychiatry. 2011; 68: 871-880
        • Hartberg C.B.
        • Sundet K.
        • Rimol L.M.
        • Haukvik U.K.
        • Lange E.H.
        • Nesvåg R.
        • et al.
        Brain cortical thickness and surface area correlates of neurocognitive performance in patients with schizophrenia, bipolar disorder, and healthy adults.
        J Int Neuropsychol Soc. 2011; 17: 1080-1093
        • Rimol L.M.
        • Hartberg C.B.
        • Nesvåg R.
        • Fennema-Notestine C.
        • Hagler D.J.
        • Pung C.J.
        • et al.
        Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder.
        Biol Psychiatry. 2010; 68: 41-50
        • Kuperberg G.R.
        • Broome M.R.
        • McGuire P.K.
        • David A.S.
        • Eddy M.
        • Ozawa F.
        • et al.
        Regionally localized thinning of the cerebral cortex in schizophrenia.
        Arch Gen Psychiatry. 2003; 60: 878-888
        • Goldman A.L.
        • Pezawas L.
        • Mattay V.S.
        • Fischl B.
        • Verchinski B.A.
        • Chen Q.
        • et al.
        Widespread reductions of cortical thickness in schizophrenia and spectrum disorders and evidence of heritability.
        Arch Gen Psychiatry. 2009; 66: 467-477
        • Fornito A.
        • Yücel M.
        • Wood S.J.
        • Adamson C.
        • Velakoulis D.
        • Saling M.M.
        • et al.
        Surface-based morphometry of the anterior cingulate cortex in first episode schizophrenia.
        Hum Brain Mapp. 2008; 29: 478-489
        • van Erp T.G.M.
        • Walton E.
        • Hibar D.P.
        • Schmaal L.
        • Jiang W.
        • Glahn D.C.
        • et al.
        Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the Enhancing Neuro Imaging Genetics Through Meta-Analysis (ENIGMA) Consortium.
        Biol Psychiatry. 2018; 84: 644-654
        • Crespo-Facorro B.
        • Roiz-Santiáñez R.
        • Pérez-Iglesias R.
        • Rodriguez-Sanchez J.M.
        • Mata I.
        • Tordesillas-Gutierrez D.
        • et al.
        Global and regional cortical thinning in first-episode psychosis patients: Relationships with clinical and cognitive features.
        Psychol Med. 2011; 41: 1449-1460
        • Yang Y.
        • Nuechterlein K.H.
        • Phillips O.
        • Hamilton L.S.
        • Subotnik K.L.
        • Asarnow R.F.
        • et al.
        The contributions of disease and genetic factors towards regional cortical thinning in schizophrenia: The UCLA family study.
        Schizophr Res. 2010; 123: 116-125
        • Narr K.L.
        • Toga A.W.
        • Szeszko P.
        • Thompson P.M.
        • Woods R.P.
        • Robinson D.
        • et al.
        Cortical thinning in cingulate and occipital cortices in first episode schizophrenia.
        Biol Psychiatry. 2005; 58: 32-40
        • Nesvåg R.
        • Lawyer G.
        • Varnäs K.
        • Fjell A.M.
        • Walhovd K.B.
        • Frigessi A.
        • et al.
        Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication.
        Schizophr Res. 2008; 98: 16-28
        • Sprooten E.
        • Papmeyer M.
        • Smyth A.M.
        • Vincenz D.
        • Honold S.
        • Conlon G.A.
        • et al.
        Cortical thickness in first-episode schizophrenia patients and individuals at high familial risk: A cross-sectional comparison.
        Schizophr Res. 2013; 151: 259-264
        • Byun M.S.
        • Kim J.S.
        • Jung W.H.
        • Jang J.H.
        • Choi J.S.
        • Kim S.N.
        • et al.
        Regional cortical thinning in subjects with high genetic loading for schizophrenia.
        Schizophr Res. 2012; 141: 197-203
        • Ziermans T.B.
        • Schothorst P.F.
        • Schnack H.G.
        • Koolschijn P.C.
        • Kahn R.S.
        • van Engeland H.
        • et al.
        Progressive structural brain changes during development of psychosis.
        Schizophr Bull. 2012; 38: 519-530
        • Jung W.H.
        • Kim J.S.
        • Jang J.H.
        • Choi J.S.
        • Jung M.H.
        • Park J.Y.
        • et al.
        Cortical thickness reduction in individuals at ultra-high-risk for psychosis.
        Schizophr Bull. 2011; 37: 839-849
        • Bois C.
        • Whalley H.C.
        • McIntosh A.M.
        • Lawrie S.M.
        Structural magnetic resonance imaging markers of susceptibility and transition to schizophrenia: A review of familial and clinical high risk population studies.
        J Psychopharmacol. 2015; 29: 144-154
        • Palaniyappan L.
        • Mallikarjun P.
        • Joseph V.
        • White T.P.
        • Liddle P.F.
        Regional contraction of brain surface area involves three large-scale networks in schizophrenia.
        Schizophr Res. 2011; 129: 163-168
        • Bois C.
        • Ronan L.
        • Levita L.
        • Whalley H.C.
        • Giles S.
        • McIntosh A.M.
        • et al.
        Cortical surface area differentiates familial high risk individuals who go on to develop schizophrenia.
        Biol Psychiatry. 2015; 78: 413-420
        • Hedman A.M.
        • van Haren N.E.M.
        • van Baal G.C.M.
        • Brouwer R.M.
        • Brans R.G.H.
        • Schnack H.G.
        • et al.
        Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia.
        Schizophr Res. 2016; 173: 192-199
        • Reus L.M.
        • Shen X.
        • Gibson J.
        • Wigmore E.
        • Ligthart L.
        • Adams M.J.
        • et al.
        Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank.
        Sci Rep. 2017; 7: 42140
        • Terwisscha van Scheltinga A.F.
        • Bakker S.C.
        • van Haren N.E.
        • Derks E.M.
        • Buizer-Voskamp J.E.
        • Boos H.B.
        • et al.
        Genetic schizophrenia risk variants jointly modulate total brain and white matter volume.
        Biol Psychiatry. 2013; 73: 525-531
        • Caseras X.
        • Tansey K.E.
        • Foley S.
        • Linden D.
        Association between genetic risk scoring for schizophrenia and bipolar disorder with regional subcortical volumes.
        Transl Psychiatry. 2015; 5: e692
        • Oertel-Knöchel V.
        • Lancaster T.M.
        • Knöchel C.
        • Stäblein M.
        • Storchak H.
        • Reinke B.
        • et al.
        Schizophrenia risk variants modulate white matter volume across the psychosis spectrum: Evidence from two independent cohorts.
        Neuroimage Clin. 2015; 7: 764-770
        • Van der Auwera S.
        • Wittfeld K.
        • Homuth G.
        • Teumer A.
        • Hegenscheid K.
        • Grabe H.J.
        No association between polygenic risk for schizophrenia and brain volume in the general population.
        Biol Psychiatry. 2015; 78: e41-e42
        • Papiol S.
        • Mitjans M.
        • Assogna F.
        • Piras F.
        • Hammer C.
        • Caltagirone C.
        • et al.
        Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample.
        Transl Psychiatry. 2014; 4: e362
        • Neilson E.
        • Bois C.
        • Gibson J.
        • Duff B.
        • Watson A.
        • Roberts N.
        • et al.
        Effects of environmental risks and polygenic loading for schizophrenia on cortical thickness.
        Schizophr Res. 2017; 184: 128-136
        • Lancaster T.M.
        • Dimitriadis S.L.
        • Tansey K.E.
        • Perry G.
        • Ihssen N.
        • Jones D.K.
        • et al.
        Structural and functional neuroimaging of polygenic risk for schizophrenia: A recall-by-genotype-based approach.
        Schizophr Bull. 2019; 45: 405-414
        • Forsyth J.K.
        • Ellman L.M.
        • Tanskanen A.
        • Mustonen U.
        • Huttunen M.O.
        • Suvisaari J.
        • et al.
        Genetic risk for schizophrenia, obstetric complications, and adolescent school outcome: Evidence for gene-environment interaction.
        Schizophr Bull. 2013; 39: 1067-1076
        • Clarke M.C.
        • Harley M.
        • Cannon M.
        The role of obstetric events in schizophrenia.
        Schizophr Bull. 2006; 32: 3-8
        • Jablensky A.V.
        • Morgan V.
        • Zubrick S.R.
        • Bower C.
        • Yellachich L.A.
        Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders.
        Am J Psychiatry. 2005; 162: 79-91
        • Rubio-Abadal E.
        • Ochoa S.
        • Barajas A.
        • Baños I.
        • Dolz M.
        • Sanchez B.
        • et al.
        Birth weight and obstetric complications determine age at onset in first episode of psychosis.
        J Psychiatr Res. 2015; 65: 108-114
        • Lærum A.M.
        • Reitan S.K.
        • Evensen K.A.
        • Lydersen S.
        • Brubakk A.M.
        • Skranes J.
        • et al.
        Psychiatric disorders and general functioning in low birth weight adults: A longitudinal study.
        Pediatrics. 2017; 139: e20162135
        • Geddes J.R.
        • Lawrie S.M.
        Obstetric complications and schizophrenia: A meta-analysis.
        Br J Psychiatry. 1995; 167: 786-793
        • Cannon M.
        • Jones P.B.
        • Murray R.M.
        Obstetric complications and schizophrenia: Historical and meta-analytic review.
        Am J Psychiatry. 2002; 159: 1080-1092
        • Van Erp T.G.
        • Saleh P.A.
        • Rosso I.M.
        • Huttunen M.
        • Lönnqvist J.
        • Pirkola T.
        • et al.
        Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers.
        Am J Psychiatry. 2002; 159: 1514-1520
        • Gielen M.
        • Lindsey P.J.
        • Derom C.
        • Smeets H.J.
        • Souren N.Y.
        • Paulussen A.D.
        • et al.
        Modeling genetic and environmental factors to increase heritability and ease the identification of candidate genes for birth weight: A twin study.
        Behav Genet. 2008; 38: 44-54
        • Lyall A.E.
        • Shi F.
        • Geng X.
        • Woolson S.
        • Li G.
        • Wang L.
        • et al.
        Dynamic development of regional cortical thickness and surface area in early childhood.
        Cereb Cortex. 2015; 25: 2204-2212
        • Walhovd K.B.
        • Fjell A.M.
        • Brown T.T.
        • Kuperman J.M.
        • Chung Y.
        • Hagler D.J.
        • et al.
        Long-term influence of normal variation in neonatal characteristics on human brain development.
        Proc Natl Acad Sci U S A. 2012; 109: 20089-20094
        • Raznahan A.
        • Greenstein D.
        • Lee N.R.
        • Clasen L.S.
        • Giedd J.N.
        Prenatal growth in humans and postnatal brain maturation into late adolescence.
        Proc Natl Acad Sci U S A. 2012; 109: 11366-11371
        • Haukvik U.K.
        • Rimol L.M.
        • Roddey J.C.
        • Hartberg C.B.
        • Lange E.H.
        • Vaskinn A.
        • et al.
        Normal birth weight variation is related to cortical morphology across the psychosis spectrum.
        Schizophr Bull. 2014; 40: 410-419
        • Li G.
        • Wang L.
        • Shi F.
        • Lyall A.E.
        • Ahn M.
        • Peng Z.
        • et al.
        Cortical thickness and surface area in neonates at high risk for schizophrenia.
        Brain Struct Funct. 2016; 221: 447-461
        • Walder D.J.
        • Faraone S.V.
        • Glatt S.J.
        • Tsuang M.T.
        • Seidman L.J.
        Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study.
        Schizophr Res. 2014; 157: 142-148
        • Cox S.R.
        • Ritchie S.J.
        • Tucker-Drob E.M.
        • Liewald D.C.
        • Hagenaars S.P.
        • Davies G.
        • et al.
        Ageing and brain white matter structure in 3,513 UK Biobank participants.
        Nat Commun. 2016; 7: 13629
        • Alfaro-Almagro F.
        • Jenkinson M.
        • Bangerter N.K.
        • Andersson J.L.R.
        • Griffanti L.
        • Douaud G.
        • et al.
        Image processing and quality control for the first 10,000 brain imaging datasets from UK Biobank.
        Neuroimage. 2017; 166: 400-424
        • Miller K.L.
        • Alfaro-Almagro F.
        • Bangerter N.K.
        • Thomas D.L.
        • Yacoub E.
        • Xu J.
        • et al.
        Multimodal population brain imaging in the UK Biobank prospective epidemiological study.
        Nat Neurosci. 2016; 19: 1523-1536
        • Desikan R.S.
        • Ségonne F.
        • Fischl B.
        • Quinn B.T.
        • Dickerson B.C.
        • Blacker D.
        • et al.
        An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.
        Neuroimage. 2006; 31: 968-980
        • Klein A.
        • Tourville J.
        101 labeled brain images and a consistent human cortical labeling protocol.
        Front Neurosci. 2012; 6: 171
        • Cox S.R.
        • Bastin M.E.
        • Ritchie S.J.
        • Dickie D.A.
        • Liewald D.C.
        • Muñoz Maniega S.
        • et al.
        Brain cortical characteristics of lifetime cognitive ageing.
        Brain Struct Funct. 2018; 223: 509-518
        • Wain L.V.
        • Shrine N.
        • Miller S.
        • Jackson V.E.
        • Ntalla I.
        • Soler Artigas M.
        • et al.
        Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): A genetic association study in UK Biobank.
        Lancet Respir Med. 2015; 3: 769-781
        • Luciano M.
        • Hagenaars S.P.
        • Davies G.
        • Hill W.D.
        • Clarke T.K.
        • Shirali M.
        • et al.
        Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism.
        Nat Genet. 2018; 50: 6-11
        • Howard D.M.
        • Adams M.J.
        • Shirali M.
        • Clarke T.K.
        • Marioni R.E.
        • Davies G.
        • et al.
        Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.
        Nat Commun. 2018; 9: 1470
        • Manichaikul A.
        • Mychaleckyj J.C.
        • Rich S.S.
        • Daly K.
        • Sale M.
        • Chen W.M.
        Robust relationship inference in genome-wide association studies.
        Bioinformatics. 2010; 26: 2867-2873
        • Bycroft C.
        • Freeman C.
        • Petkova D.
        • Band G.
        • Elliott L.T.
        • Sharp K.
        • et al.
        The UK Biobank resource with deep phenotyping and genomic data.
        Nature. 2018; 563: 203-209
        • Purcell S.
        • Neale B.
        • Todd-Brown K.
        • Thomas L.
        • Ferreira M.A.
        • Bender D.
        • et al.
        PLINK: A tool set for whole-genome association and population-based linkage analyses.
        Am J Hum Genet. 2007; 81: 559-575
        • Wray N.R.
        • Ripke S.
        • Mattheisen M.
        • Trzaskowski M.
        • Byrne E.M.
        • Abdellaoui A.
        • et al.
        Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
        Nat Genet. 2018; 50: 668-681
        • Shenkin S.D.
        • Zhang M.G.
        • Der G.
        • Mathur S.
        • Mina T.H.
        • Reynolds R.M.
        Validity of recalled v. recorded birth weight: A systematic review and meta-analysis.
        J Dev Orig Health Dis. 2017; 8: 137-148
        • Shen X.
        • Reus L.M.
        • Cox S.R.
        • Adams M.J.
        • Liewald D.C.
        • Bastin M.E.
        • et al.
        Subcortical volume and white matter integrity abnormalities in major depressive disorder: Findings from UK Biobank imaging data.
        Sci Rep. 2017; 7: 5547
        • Genovese C.R.
        • Lazar N.A.
        • Nichols T.
        Thresholding of statistical maps in functional neuroimaging using the false discovery rate.
        Neuroimage. 2002; 15: 870-878
        • Neilson E.
        • Bois C.
        • Clarke T.K.
        • Hall L.
        • Johnstone E.C.
        • Owens D.G.C.
        • et al.
        Polygenic risk for schizophrenia, transition and cortical gyrification: A high-risk study.
        Psychol Med. 2018; 48: 1532-1539
        • Lawrie S.M.
        • Whalley H.C.
        • Abukmeil S.S.
        • Kestelman J.N.
        • Donnelly L.
        • Miller P.
        • et al.
        Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia.
        Biol Psychiatry. 2001; 49: 811-823
        • Lee P.H.
        • Baker J.T.
        • Holmes A.J.
        • Jahanshad N.
        • Ge T.
        • Jung J.Y.
        • et al.
        Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.
        Mol Psychiatry. 2016; 21: 1680-1689
        • Consortium SPG-WASG
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Wylie K.P.
        • Tregellas J.R.
        The role of the insula in schizophrenia.
        Schizophr Res. 2010; 123: 93-104
        • Plomin R.
        Commentary: Missing heritability, polygenic scores, and gene-environment correlation.
        J Child Psychol Psychiatry. 2013; 54: 1147-1149
        • Martinussen M.
        • Fischl B.
        • Larsson H.B.
        • Skranes J.
        • Kulseng S.
        • Vangberg T.R.
        • et al.
        Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method.
        Brain. 2005; 128: 2588-2596
        • Horikoshi M.
        • Beaumont R.N.
        • Day F.R.
        • Warrington N.M.
        • Kooijman M.N.
        • Fernandez-Tajes J.
        • et al.
        Genome-wide associations for birth weight and correlations with adult disease.
        Nature. 2016; 538: 248-252
        • Horikoshi M.
        • Yaghootkar H.
        • Mook-Kanamori D.O.
        • Sovio U.
        • Taal H.R.
        • Hennig B.J.
        • et al.
        New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
        Nat Genet. 2013; 45: 76-82
        • Dudbridge F.
        Power and predictive accuracy of polygenic risk scores.
        PLoS Genet. 2013; 9: e1003348
        • Liuhanen J.
        • Suvisaari J.
        • Kajantie E.
        • Miettunen J.
        • Sarin A.P.
        • Järvelin M.R.
        • et al.
        Interaction between compound genetic risk for schizophrenia and high birth weight contributes to social anhedonia and schizophrenia in women.
        Psychiatry Res. 2017; 259: 148-153
        • Reginsson G.W.
        • Ingason A.
        • Euesden J.
        • Bjornsdottir G.
        • Olafsson S.
        • Sigurdsson E.
        • et al.
        Polygenic risk scores for schizophrenia and bipolar disorder associate with addiction.
        Addict Biol. 2018; 23: 485-492
        • Taylor M.
        • Simpkin A.J.
        • Haycock P.C.
        • Dudbridge F.
        • Zuccolo L.
        Exploration of a polygenic risk score for alcohol consumption: A longitudinal analysis from the ALSPAC Cohort.
        PLoS One. 2016; 11: e0167360
        • Dima D.
        • Breen G.
        Polygenic risk scores in imaging genetics: Usefulness and applications.
        J Psychopharmacol. 2015; 29: 867-871
        • Thompson P.M.
        • Stein J.L.
        • Medland S.E.
        • Hibar D.P.
        • Vasquez A.A.
        • Renteria M.E.
        • et al.
        The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data.
        Brain Imaging Behav. 2014; 8: 153-182
        • Schnack H.G.
        • van Haren N.E.
        • Brouwer R.M.
        • van Baal G.C.
        • Picchioni M.
        • Weisbrod M.
        • et al.
        Mapping reliability in multicenter MRI: Voxel-based morphometry and cortical thickness.
        Hum Brain Mapp. 2010; 31: 1967-1982
        • Liu B.
        • Zhang X.
        • Cui Y.
        • Qin W.
        • Tao Y.
        • Li J.
        • et al.
        Polygenic risk for schizophrenia influences cortical gyrification in 2 independent general populations.
        Schizophr Bull. 2017; 43: 673-680
        • Habets P.
        • Marcelis M.
        • Gronenschild E.
        • Drukker M.
        • van Os J.
        • Genetic Risk and Outcome of Psychosis (G.R.O.U.P)
        Reduced cortical thickness as an outcome of differential sensitivity to environmental risks in schizophrenia.
        Biol Psychiatry. 2011; 69: 487-494
        • French L.
        • Gray C.
        • Leonard G.
        • Perron M.
        • Pike G.B.
        • Richer L.
        • et al.
        Early cannabis use, polygenic risk score for schizophrenia and brain maturation in adolescence.
        JAMA Psychiatry. 2015; 72: 1002-1011

      Linked Article