Advertisement

Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia

Published:February 06, 2019DOI:https://doi.org/10.1016/j.biopsych.2019.01.023

      Abstract

      Background

      Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium.

      Methods

      Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents’ genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients’ early onset of schizophrenia (≤18 years old) on paternal age was conducted.

      Results

      Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients’ early onset of schizophrenia remained (odds ratio = 1.29, p = .04).

      Conclusions

      The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.

      Keywords

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

      Purchase one-time access:

      Academic and Personal

      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

        • Malaspina D.
        • Harlap S.
        • Fennig S.
        • Heiman D.
        • Nahon D.
        • Feldman D.
        • et al.
        Advancing paternal age and the risk of schizophrenia.
        Arch Gen Psychiatry. 2001; 58: 361-367
        • Reichenberg A.
        • Gross R.
        • Weiser M.
        • Bresnahan M.
        • Silverman J.
        • Harlap S.
        • et al.
        Advancing paternal age and autism.
        Arch Gen Psychiatry. 2006; 63: 1026-1032
        • Frans E.M.
        • Sandin S.
        • Reichenberg A.
        • Lichtenstein P.
        • Langstrom N.
        • Hultman C.M.
        Advancing paternal age and bipolar disorder.
        Arch Gen Psychiatry. 2008; 65: 1034-1040
        • Miller B.
        • Messias E.
        • Miettunen J.
        • Alaräisänen A.
        • Järvelin M.R.
        • Koponen H.
        • et al.
        Meta-analysis of paternal age and schizophrenia risk in male versus female offspring.
        Schizophr Bull. 2011; 37: 1039-1047
        • Frans E.M.
        • Sandin S.
        • Reichenberg A.
        • Langstrom N.
        • Lichtenstein P.
        • McGrath J.J.
        • et al.
        Autism risk across generations: A population-based study of advancing grandpaternal and paternal age.
        JAMA Psychiatry. 2013; 70: 516-521
        • D’Onofrio B.M.
        • Rickert M.E.
        • Frans E.
        • Kuja-Halkola R.
        • Almqvist C.
        • Sjolander A.
        • et al.
        Paternal age at childbearing and offspring psychiatric and academic morbidity.
        JAMA Psychiatry. 2014; 71: 432-438
        • McGrath J.J.
        • Petersen L.
        • Agerbo E.
        • Mors O.
        • Mortensen P.B.
        • Pedersen C.B.
        A comprehensive assessment of parental age and psychiatric disorders.
        JAMA Psychiatry. 2014; 71: 301-309
        • de Kluiver H.
        • Buizer-Voskamp J.E.
        • Dolan C.V.
        • Boomsma D.I.
        Paternal age and psychiatric disorders: A review.
        Am J Med Genet B Neuropsychiatr Genet. 2017; 174B: 202-213
        • Frans E.M.
        • McGrath J.J.
        • Sandin S.
        • Lichtenstein P.
        • Reichenberg A.
        • Langstrom N.
        • et al.
        Advanced paternal and grandpaternal age and schizophrenia: A three-generation perspective.
        Schizophr Res. 2011; 133: 120-124
        • Fond G.
        • Godin O.
        • Boyer L.
        • Llorca P.M.
        • Andrianarisoa M.
        • Brunel L.
        • et al.
        Advanced paternal age is associated with earlier schizophrenia onset in offspring. Results from the national multicentric FACE-SZ cohort.
        Psychiatry Res. 2017; 254: 218-223
        • Wang S.H.
        • Liu C.M.
        • Hwu H.G.
        • Hsiao C.K.
        • Chen W.J.
        Association of older paternal age with earlier onset among co-affected schizophrenia sib-pairs.
        Psychol Med. 2015; 45: 2205-2213
        • Malaspina D.
        Paternal factors and schizophrenia risk: De novo mutations and imprinting.
        Schizophr Bull. 2001; 27: 379-393
        • Buwe A.
        • Guttenbach M.
        • Schmid M.
        Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa.
        Cytogenet Genome Res. 2005; 111: 213-228
        • Goriely A.
        • McGrath J.J.
        • Hultman C.M.
        • Wilkie A.O.M.
        • Malaspina D.
        “Selfish spermatogonial selection”: A novel mechanism for the association between advanced paternal age and neurodevelopmental disorders.
        Am J Psychiatry. 2013; 170: 599-608
        • Kong A.
        • Frigge M.L.
        • Masson G.
        • Besenbacher S.
        • Sulem P.
        • Magnusson G.
        • et al.
        Rate of de novo mutations and the importance of father’s age to disease risk.
        Nature. 2012; 488: 471-475
        • Goldmann J.M.
        • Wong W.S.
        • Pinelli M.
        • Farrah T.
        • Bodian D.
        • Stittrich A.B.
        • et al.
        Parent-of-origin-specific signatures of de novo mutations.
        Nat Genet. 2016; 48: 935-939
        • Petersen L.
        • Mortensen P.B.
        • Pedersen C.B.
        Paternal age at birth of first child and risk of schizophrenia.
        Am J Psychiatry. 2011; 168: 82-88
        • Pedersen C.B.
        • McGrath J.
        • Mortensen P.B.
        • Petersen L.
        The importance of father’s age to schizophrenia risk.
        Mol Psychiatry. 2014; 19: 530-531
        • Ek M.
        • Wicks S.
        • Svensson A.C.
        • Idring S.
        • Dalman C.
        Advancing paternal age and schizophrenia: The impact of delayed fatherhood.
        Schizophr Bull. 2015; 41: 708-714
        • Mehta D.
        • Tropf F.C.
        • Gratten J.
        • Bakshi A.
        • Zhu Z.
        • Bacanu S.A.
        • et al.
        Evidence for genetic overlap between schizophrenia and age at first birth in women.
        JAMA Psychiatry. 2016; 73: 497-505
        • Ni G.
        • Gratten J.
        • Wray N.R.
        • Lee S.H.
        Age at first birth in women is genetically associated with increased risk of schizophrenia.
        Sci Rep. 2018; 8: 10168
        • Ahn K.
        • An S.
        • Shugart Y.Y.
        • Rapoport J.
        Common polygenic variation and risk for childhood-onset schizophrenia.
        Mol Psychiatry. 2016; 21: 94-96
        • Power R.A.
        • Tansey K.E.
        • Buttenschøn H.N.
        • Cohen-Woods S.
        • Bigdeli T.
        • Hall L.S.
        • et al.
        Genome-wide association for major depression through age at onset stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.
        Biol Psychiatry. 2017; 81: 325-335
        • Woolston A.L.
        • Hsiao P.C.
        • Kuo P.H.
        • Wang S.H.
        • Lien Y.J.
        • Liu C.M.
        • et al.
        Genetic loci associated with an earlier age at onset in multiplex schizophrenia.
        Sci Rep. 2017; 7: 6486
        • Wang S.H.
        • Hsiao P.C.
        • Yeh L.L.
        • Liu C.M.
        • Liu C.C.
        • Hwang T.J.
        • et al.
        Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia.
        Genes Brain Behav. 2018; 17: 49-55
        • Nurnberger Jr., J.I.
        • Blehar M.C.
        • Kaufmann C.A.
        • York-Cooler C.
        • Simpson S.G.
        • Harkavy-Friedman J.
        • et al.
        Diagnostic Interview for Genetic Studies: Rationale, unique features, and training.
        Arch Gen Psychiatry. 1994; 51: 849-859
        • Chen W.J.
        • Liu S.K.
        • Chang C.J.
        • Lien Y.J.
        • Chang Y.H.
        • Hwu H.G.
        Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients.
        Am J Psychiatry. 1998; 155: 1214-1220
        • Chang C.J.
        • Chen W.J.
        • Liu S.K.
        • Cheng J.J.
        • Yang W.C.
        • Chang H.J.
        • et al.
        Morbidity risk of psychiatric disorders among the first degree relatives of schizophrenia patients in Taiwan.
        Schizophr Bull. 2002; 28: 379-392
        • Gogtay N.
        • Vyas N.S.
        • Testa R.
        • Wood S.J.
        • Pantelis C.
        Age of onset of schizophrenia: Perspectives from structural neuroimaging studies.
        Schizophr Bull. 2011; 37: 504-513
        • Vyas N.S.
        • Patel N.H.
        • Puri B.K.
        Neurobiology and phenotypic expression in early onset schizophrenia.
        Early Interv Psychiatry. 2011; 5: 3-14
        • Ahn K.
        • Gotay N.
        • Andersen T.
        • Anvari A.
        • Gochman P.
        • Lee Y.
        • et al.
        High rate of disease-related copy number variations in childhood onset schizophrenia.
        Mol Psychiatry. 2014; 19: 568-572
        • Schizophrenia Psychiatric Genome-Wide Association Study Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • 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
        • Miller B.
        • Suvisaari J.
        • Miettunen J.
        • Jarvelin M.R.
        • Haukka J.
        • Tanskanen A.
        • et al.
        Advanced paternal age and parental history of schizophrenia.
        Schizophr Res. 2011; 133: 125-132
        • Frans E.
        • Lichtenstein P.
        • Hultman C.
        • Kuja-Halkola R.
        Age at fatherhood: Heritability and associations with psychiatric disorders.
        Psychol Med. 2016; 46: 2981-2988
        • Janecka M.
        • Mill J.
        • Basson M.
        • Goriely A.
        • Spiers H.
        • Reichenberg A.
        • et al.
        Advanced paternal age effects in neurodevelopmental disorders—review of potential underlying mechanisms.
        Transl Psychiatry. 2017; 7: e1019
        • Schizophrenia Psychiatric Genome-Wide Association Study Consortium
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Martin A.R.
        • Gignoux C.R.
        • Walters R.K.
        • Wojcik G.L.
        • Neale B.M.
        • Gravel S.
        • et al.
        Human demographic history impacts genetic risk prediction across diverse populations.
        Am J Hum Genet. 2017; 100: 635-649
      1. Lam M, Chen CY, Li Z, Martin A, Bryois J, Ma X, et al. (2018): Comparative genetic architectures of schizophrenia in East Asian and European populations [published online ahead of print Oct 18]. bioRxiv.

        • Gratten J.
        • Wray N.R.
        • Peyrot W.J.
        • McGrath J.J.
        • Visscher P.M.
        • Goddard M.E.
        Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations.
        Nat Genet. 2016; 48: 718-724
        • Perrin M.C.
        • Brown A.S.
        • Malaspina D.
        Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia.
        Schizophr Bull. 2007; 33: 1270-1273
        • Atsem S.
        • Reichenbach J.
        • Potabattula R.
        • Dittrich M.
        • Nava C.
        • Depienne C.
        • et al.
        Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation.
        Hum Mol Genet. 2016; 25: 4996-5005
        • Auroux M.
        • Nawar N.N.
        • Naguib M.
        • Baud M.
        • Lapaquellerie N.
        Post-pubescent to mature fathers: Increase in progeny quality?.
        Hum Reprod. 1998; 13: 55-59
        • Bray I.
        • Gunnell D.
        • Davey Smith G.
        Advanced paternal age: How old is too old?.
        J Epidemiol Community Health. 2006; 60: 851-853