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Risk in Relatives, Heritability, SNP-Based Heritability, and Genetic Correlations in Psychiatric Disorders: A Review

      Abstract

      The genetic contribution to psychiatric disorders is observed through the increased rates of disorders in the relatives of those diagnosed with disorders. These increased rates are observed to be nonspecific; for example, children of those with schizophrenia have increased rates of schizophrenia but also a broad range of other psychiatric diagnoses. While many factors contribute to risk, epidemiological evidence suggests that the genetic contribution carries the highest risk burden. The patterns of inheritance are consistent with a polygenic architecture of many contributing risk loci. The genetic studies of the past decade have provided empirical evidence identifying thousands of DNA variants associated with psychiatric disorders. Here, we describe how these latest results are consistent with observations from epidemiology. We provide an R tool (CHARRGe) to calculate genetic parameters from epidemiological parameters and vice versa. We discuss how the single nucleotide polymorphism–based estimates of heritability and genetic correlation relate to those estimated from family records.

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      References

        • Bleuler E.
        Mendelismus bei Psychosen, speziell bei der Schizophrenie [Mendelism in the psychoses, especially schizophrenia].
        Arch Neurol Psychiatr. 1917; 1: 19-40
        • Kendler K.S.
        Eugen Bleuler’s views on the genetics of schizophrenia in 1917.
        Schizophr Bull. 2020; 1–7
        • Rüdin E.
        Studien uber Vererbung und entstehung geistiger Störungen. I. Zur vererbung und neuentstehung der Dementia praecox [Studies on the inheritance and origin of mental illness. I. The problem of the inheritance and primary origin of dementia praecox].
        (Monographien aus dem Gesamtgebiet der Neurologie und Psychiatrie, vol. 12) Springer, Berlin1916
        • Kendler K.S.
        • Zerbin-Rüdin E.
        Abstract and review of “Studien über Vererbung und Entstehung Geistiger Störungen. I. Zur Vererbung und Neuentstehung der Dementia Praecox.” (Studies on the inheritance and origin of mental illness: I. To the problem of the inheritance and primary origin of dementia praecox).
        Am J Med Genet. 1996; 67: 338-342
        • Mortensen P.B.
        • Pedersen M.G.
        • Pedersen C.B.
        Psychiatric family history and schizophrenia risk in Denmark: Which mental disorders are relevant?.
        Psychol Med. 2010; 40: 201-210
        • Bøcker C.
        • Pedersen C.
        The Danish Civil Registration System. A cohort of eight million persons.
        Dan Med Bull. 2006; 53: 441-449
        • Ekbom A.
        The Swedish multi-generation register.
        Methods Mol Biol. 2011; 675: 215-220
        • Hilker R.
        • Helenius D.
        • Fagerlund B.
        • Skytthe A.
        • Christensen K.
        • Werge T.M.
        • et al.
        Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish Twin Register.
        Biol Psychiatry. 2018; 83: 492-498
        • Nordsletten A.E.
        • Brander G.
        • Larsson H.
        • Lichtenstein P.
        • Crowley J.J.
        • Sullivan P.F.
        • et al.
        Evaluating the impact of nonrandom mating: Psychiatric outcomes among the offspring of pairs diagnosed with schizophrenia and bipolar disorder.
        Biol Psychiatry. 2019; 87: 253-262
        • Cederlöf M.
        • Thornton L.M.
        • Baker J.
        • Lichtenstein P.
        • Larsson H.
        • Rück C.
        • et al.
        Etiological overlap between obsessive-compulsive disorder and anorexia nervosa: A longitudinal cohort, multigenerational family and twin study.
        World Psychiatry. 2015; 14: 333-338
        • Lichtenstein P.
        • Carlström E.
        • Råstam M.
        • Gillberg C.
        • Anckarsäter H.
        The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.
        Am J Psychiatry. 2010; 167: 1357-1363
        • Stahl E.A.
        • Breen G.
        • Forstner A.J.
        • McQuillin A.
        • Ripke S.
        • Trubetskoy V.
        • et al.
        Genome-wide association study identifies 30 loci associated with bipolar disorder.
        Nat Genet. 2019; 51: 793-803
        • Cross-Disorder Group of the Psychiatric Genomics Consortium
        Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.
        Cell. 2019; 179: 1469-1482, e11
        • Zeng J.
        • De Vlaming R.
        • Wu Y.
        • Robinson M.R.
        • Lloyd-Jones L.R.
        • Yengo L.
        • et al.
        Signatures of negative selection in the genetic architecture of human complex traits.
        Nat Genet. 2018; 50: 746-753
        • Ripke S.
        • Neale B.M.
        • Corvin A.
        • Walters J.T.R.
        • Farh K.H.
        • Holmans P.A.
        • et al.
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Baker J.H.
        • Schaumberg K.
        • Munn-Chernoff M.A.
        Genetics of anorexia nervosa.
        Curr Psychiatry Rep. 2017; 19: 84
        • Lee S.H.
        • Ripke S.
        • Neale B.M.
        • Faraone S.V.
        • Purcell S.M.
        • Perlis R.H.
        • et al.
        Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
        Nat Genet. 2013; 45: 984-994
        • Nordsletten A.E.
        • Larsson H.
        • Crowley J.J.
        • Almqvist C.
        • Lichtenstein P.
        • Mataix-Cols D.
        Patterns of nonrandom mating within and across 11 major psychiatric disorders.
        JAMA Psychiatry. 2016; 73: 354-361
        • Van Snellenberg J.X.
        • De Candia T.
        Meta-analytic evidence for familial coaggregation of schizophrenia and bipolar disorder.
        Arch Gen Psychiatry. 2009; 66: 748-755
        • Lichtenstein P.
        • Yip B.H.
        • Björk C.
        • Pawitan Y.
        • Cannon T.D.
        • Sullivan P.F.
        • Hultman C.M.
        Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study.
        Lancet. 2009; 373: 234-239
        • Sullivan P.F.
        • Magnusson C.
        • Reichenberg A.
        • Boman M.
        • Dalman C.
        • Davidson M.
        • et al.
        Family history of schizophrenia and bipolar disorder as risk factors for autism.
        Arch Gen Psychiatry. 2012; 69: 1099-1103
        • Harper P.S.
        • Newcombe R.G.
        Age at onset and life table risks in genetic counselling for Huntington’s disease.
        J Med Genet. 1992; 29: 239-242
        • Falconer D.S.
        The inheritance of liability to certain diseases, estimated from the incidence among relatives.
        Ann Hum Genet. 1965; 29: 51-76
        • Pringsheim T.
        • Wiltshire K.
        • Day L.
        • Dykeman J.
        • Steeves T.
        • Jette N.
        The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis.
        Mov Disord. 2012; 27: 1083-1091
        • Holtzman C.W.
        • Trotman H.D.
        • Goulding S.M.
        • Ryan A.T.
        • MacDonald A.N.
        • Shapiro D.I.
        • et al.
        Stress and neurodevelopmental processes in the emergence of psychosis.
        Neuroscience. 2013; 249: 172-191
        • Agnew-Blais J.
        • Danese A.
        Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: A systematic review and meta-analysis.
        Lancet Psychiatry. 2016; 3: 342-349
        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Kessler R.C.
        • Aguilar-Gaxiola S.
        • Alonso J.
        • Bromet E.J.
        • Gureje O.
        • Karam E.G.
        • et al.
        The associations of earlier trauma exposures and history of mental disorders with PTSD after subsequent traumas.
        Mol Psychiatry. 2018; 23: 1892-1899
        • Coleman J.R.I.
        • Peyrot W.J.
        • Purves K.L.
        • Davis K.A.S.
        • Rayner C.
        • Choi S.W.
        • et al.
        Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank.
        Mol Psychiatry. 2020; 25: 1430-1446
        • Rees E.
        • Han J.
        • Morgan J.
        • Carrera N.
        • Escott-Price V.
        • Pocklington A.J.
        • et al.
        De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia.
        Nat Neurosci. 2020; 23: 179-184
        • Yuen R.K.C.
        • Merico D.
        • Cao H.
        • Pellecchia G.
        • Alipanahi B.
        • Thiruvahindrapuram B.
        • et al.
        Genome-wide characteristics of de novo mutations in autism.
        NPJ Genomic Med. 2016; 1: 160271-1692710
        • Li J.
        • Cai T.
        • Jiang Y.
        • Chen H.
        • He X.
        • Chen C.
        • et al.
        Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.
        Mol Psychiatry. 2016; 21: 290-297
        • Lee J.M.
        • Wheeler V.C.
        • Chao M.J.
        • Vonsattel J.P.G.
        • Pinto R.M.
        • Lucente D.
        • et al.
        Identification of genetic factors that modify clinical onset of Huntington’s disease.
        Cell. 2015; 162: 516-526
        • Reich T.
        • James J.W.
        • Morris C.A.
        The use of multiple thresholds in determining the mode of transmission of semi-continuous traits.
        Ann Hum Genet. 1972; 36: 163-184
        • Visscher P.M.
        • Medland S.E.
        • Ferreira M.A.R.
        • Morley K.I.
        • Zhu G.
        • Cornes B.K.
        • et al.
        Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings.
        PLoS Genet. 2006; 2: 0316-0325
        • Visscher P.M.
        • Gordon S.
        • Neale M.C.
        Power of the classical twin design revisited: II detection of common environmental variance.
        Twin Res Hum Genet. 2008; 11: 48-54
        • Visscher P.M.
        Power of the classical twin design revisited.
        Twin Res. 2004; 7: 505-512
        • Gottesman II,
        • Laursen T.M.
        • Bertelsen A.
        • Mortensen P.B.
        Severe mental disorders in offspring with 2 psychiatrically ill parents.
        Arch Gen Psychiatry. 2010; 67: 252-257
        • Wray N.R.
        • Gottesman II,
        Using summary data from the Danish National Registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder.
        Front Genet. 2012; 3: 118
        • Stringer S.
        • Derks E.M.
        • Kahn R.S.
        • Hill W.G.
        • Wray N.R.
        Assumptions and properties of limiting pathway models for analysis of epistasis in complex traits.
        PLoS One. 2013; 8e68913
        • Wray N.R.
        • Maier R.
        Genetic basis of complex genetic disease: The contribution of disease heterogeneity to missing heritability.
        Curr Epidemiol Rep. 2014; 1: 220-227
        • Yang J.
        • Zeng J.
        • Goddard M.E.
        • Wray N.R.
        • Visscher P.M.
        Concepts, estimation and interpretation of SNP-based heritability.
        Nat Genet. 2017; 49: 1304-1310
        • Wainschtein P.
        • Jain D.P.
        • Yengo L.
        • Zheng Z.
        • Cupples L.A.
        • Shadyab A.H.
        • et al.
        Recovery of trait heritability from whole genome sequence data.
        bioRxiv. 2019; https://doi.org/10.1101/588020
        • Yang J.
        • Benyamin B.
        • McEvoy B.P.
        • Gordon S.
        • Henders A.K.
        • Nyholt D.R.
        • et al.
        Common SNPs explain a large proportion of the heritability for human height.
        Nat Genet. 2010; 42: 565-569
        • Yang J.
        • Lee S.H.
        • Goddard M.E.
        • Visscher P.M.
        GCTA: A tool for genome-wide complex trait analysis.
        Am J Hum Genet. 2011; 88: 76-82
        • Bulik-Sullivan B.
        • Loh P.R.
        • Finucane H.K.
        • Ripke S.
        • Yang J.
        • Patterson N.
        • et al.
        LD score regression distinguishes confounding from polygenicity in genome-wide association studies.
        Nat Genet. 2015; 47: 291-295
        • Lloyd-Jones L.R.
        • Zeng J.
        • Sidorenko J.
        • Yengo L.
        • Moser G.
        • Kemper K.E.
        • et al.
        Improved polygenic prediction by Bayesian multiple regression on summary statistics.
        Nat Commun. 2019; 10: 5086
        • Zeng J.
        • Xue A.
        • Jiang L.
        • Lloyd-Jones L.R.
        • Wu Y.
        • Wang H.
        • et al.
        Bayesian analysis of GWAS summary data reveals differential signatures of natural selection across human complex traits and functional genomic categories.
        bioRxiv. 2019; https://doi.org/10.1101/752527
        • Yang J.
        • Bakshi A.
        • Zhu Z.
        • Hemani G.
        • Vinkhuyzen A.A.E.
        • Lee S.H.
        • et al.
        Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.
        Nat Genet. 2015; 47: 1114-1120
        • Speed D.
        • Hemani G.
        • Johnson M.R.
        • Balding D.J.
        Improved heritability estimation from genome-wide SNPs.
        Am J Hum Genet. 2012; 91: 1011-1021
        • Yang J.
        • Manolio T.A.
        • Pasquale L.R.
        • Boerwinkle E.
        • Caporaso N.
        • Cunningham J.M.
        • et al.
        Genome partitioning of genetic variation for complex traits using common SNPs.
        Nat Genet. 2011; 43: 519-525
        • Speed D.
        • Cai N.
        • Johnson M.R.
        • Nejentsev S.
        • Balding D.J.
        Reevaluation of SNP heritability in complex human traits.
        Nat Genet. 2017; 49: 986-992
        • Zaitlen N.
        • Kraft P.
        • Patterson N.
        • Pasaniuc B.
        • Bhatia G.
        • Pollack S.
        • Price A.L.
        Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.
        PLoS Genet. 2013; 9e1003520
        • Evans L.M.
        • Tahmasbi R.
        • Vrieze S.I.
        • Abecasis G.R.
        • Das S.
        • Gazal S.
        • et al.
        Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits.
        Nat Genet. 2018; 50: 737-745
        • Zheng J.
        • Erzurumluoglu A.M.
        • Elsworth B.L.
        • Kemp J.P.
        • Howe L.
        • Haycock P.C.
        • et al.
        LD Hub: A centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.
        Bioinformatics. 2017; 33: 272-279
        • Lee S.H.
        • Wray N.R.
        • Goddard M.E.
        • Visscher P.M.
        Estimating missing heritability for disease from genome-wide association studies.
        Am J Hum Genet. 2011; 88: 294-305
        • Yap C.X.
        • Sirodenko J.
        • Marioni R.E.
        • Yengo L.
        • Wray N.R.
        • Visscher P.M.
        Misestimation of heritability and prediction accuracy of male-pattern baldness.
        Nat Commun. 2018; 9: 2537
        • Gianola D.
        Heritability of polychotomous characters.
        Genetics. 1979; 93: 1051-1055
        • Peyrot W.J.
        • Boomsma D.I.
        • Penninx B.W.J.H.
        • Wray N.R.
        Disease and polygenic architecture: avoid trio design and appropriately account for unscreened control subjects for common disease.
        Am J Hum Genet. 2016; 98: 382-391
        • Lee S.H.
        • Yang J.
        • Goddard M.E.
        • Visscher P.M.
        • Wray N.R.
        Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.
        Bioinformatics. 2012; 28: 2540-2542
        • Bulik-Sullivan B.
        • Finucane H.K.
        • Anttila V.
        • Gusev A.
        • Day F.R.
        • Loh P.R.
        • et al.
        An atlas of genetic correlations across human diseases and traits.
        Nat Genet. 2015; 47: 1236-1241
        • van Rheenen W.
        • Peyrot W.J.
        • Schork A.J.
        • Lee S.H.
        • Wray N.R.
        Genetic correlations of polygenic disease traits: From theory to practice.
        Nat Rev Genet. 2019; 20: 567-581
        • The Brainstorm Consortium
        Analysis of shared heritability in common disorders of the brain.
        Science. 2018; 360eaap8757
        • Wray N.R.
        • Lee S.H.
        • Kendler K.S.
        Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes.
        Eur J Hum Genet. 2012; 20: 668-674
        • Cai N.
        • Revez J.A.
        • Adams M.J.
        • Andlauer T.F.M.
        • Breen G.
        • Byrne E.M.
        • et al.
        Minimal phenotyping yields genome-wide association signals of low specificity for major depression.
        Nat Genet. 2020; 52: 437-447
        • Brown B.C.
        • Ye C.J.
        • Price A.L.
        • Zaitlen N.
        Transethnic genetic-correlation estimates from summary statistics.
        Am J Hum Genet. 2016; 99: 76-88
        • Lam M.
        • Chen C.Y.
        • Li Z.
        • Martin A.R.
        • Bryois J.
        • Ma X.
        • et al.
        Comparative genetic architectures of schizophrenia in East Asian and European populations.
        Nat Genet. 2019; 51: 1670-1678
        • Maier R.
        • Moser G.
        • Chen G.B.
        • Ripke S.
        • Coryell W.
        • Potash J.B.
        • et al.
        Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.
        Am J Hum Genet. 2015; 96: 283-294
        • Stilo S.A.
        • Murray R.M.
        Non-genetic factors in schizophrenia.
        Curr Psychiatry Rep. 2019; 21
        • Smoller J.W.
        • Andreassen O.A.
        • Edenberg H.J.
        • Faraone S.V.
        • Glatt S.J.
        • Kendler K.S.
        Psychiatric genetics and the structure of psychopathology.
        Mol Psychiatry. 2019; 24: 409-420
        • Revez J.A.
        • Lin T.
        • Qiao Z.
        • Xue A.
        • Holtz Y.
        • Zhu Z.
        • et al.
        Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration.
        Nat Commun. 2020; 11: 1647
        • McGrath J.J.
        • Eyles D.W.
        • Pedersen C.B.
        • Anderson C.
        • Ko P.
        • Burne T.
        • Mortensen P.
        Neonatal vitamin D status and risk of schizophrenia: A population-based case-control study.
        Arch Gen Psychiatry. 2010; 67: 889-894
        • McGrath J.
        • Saari K.
        • Hakko H.
        • Jokelainen J.
        • Jones P.
        • Järvelin M.R.
        • et al.
        Vitamin D supplementation during the first year of life and risk of schizophrenia: A Finnish birth cohort study.
        Schizophr Res. 2004; 67: 237-245
        • Gottesman I.I.
        A Series of Books in Psychology. Schizophrenia Genesis: The Origins of Madness.
        WH Freeman/Times Books/Henry Holt & Co., New York1991