Large-scale genomics unveils the genetic architecture of psychiatric disorders (original) (raw)

• Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010).
  Article PubMed Google Scholar
• Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009).
  Article CAS PubMed Google Scholar
• Ronald, A. & Hoekstra, R.A. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156B, 255–274 (2011).
  Article PubMed Google Scholar
• Sullivan, P.F., Kendler, K.S. & Neale, M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003).
  Article PubMed Google Scholar
• Wray, N.R. & Gottesman, I.I. Using summary data from the Danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Front. Genet. 3, 118 (2012).
  Article PubMed PubMed Central Google Scholar
• Eyre-Walker, A. Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc. Natl. Acad. Sci. USA 107 Suppl 1, 1752–1756 (2010).
  Article PubMed PubMed Central Google Scholar
• Keller, M.C. & Miller, G. Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behav. Brain Sci. 29, 385–452 (2006).
  Article PubMed Google Scholar
• McClellan, J. & King, M.-C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
  CAS PubMed Google Scholar
• Hill, W.G., Goddard, M.E. & Visscher, P.M. Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet. 4, e1000008 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Corvin, A., Craddock, N. & Sullivan, P.F. Genome-wide association studies: a primer. Psychol. Med. 40, 1063–1077 (2010).
  Article CAS PubMed Google Scholar
• Visscher, P.M., Brown, M.A., McCarthy, M.I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• McCarroll, S.A., Feng, G. & Hyman, S.E. Genome-scale neurogenetics: methodology and meaning. Nat. Neurosci. 17, 756–763 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Psychiatric Genomics Consortium Schizophrenia Working Group. Psychiatric Genomics Consortium quadruples schizophrenia GWAS sample-size to 35,000 cases and 47,000 controls. in XXIst World Congress of Psychiatric Genetics: Redefining Mental Illness Through Genetics (Boston, 2013). This conference paper reported the identification of more than 100 loci for schizophrenia, the 'flagship' disorder of the Psychiatric Genomics Consortium. The results show what might be achieved for other psychiatric disorders as sample sizes increase.
• European Alzheimer's Disease Initiative et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).
• Charney, A.W. et al. Bipolar disorder GWAS of 13,741 cases and 19,762 controls identifies eight genome-wide significant hits and implicates genes targeted by FMRP protein. in XXIst World Congress of Psychiatric Genetics: Redefining Mental Illness Through Genetics (Boston, 2013).
  Google Scholar
• Anney, R. et al. Meta-analysis of European ancestry individuals with autism spectrum disorder reveals strong association 3′ of the astrotactin 2 (ASTN2) gene locus on chromosome 9. in XXIst World Congress of Psychiatric Genetics: Redefining Mental Illness Through Genetics (Boston, 2013).
  Google Scholar
• Neale, B.M. et al. Case-control genome-wide association study of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 49, 906–920 (2010).
  Article PubMed PubMed Central Google Scholar
• Wang, K. et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol. Psychiatry 16, 949–959 (2011).
  Article CAS PubMed Google Scholar
• Ripke, S. et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013).
  Article CAS PubMed Google Scholar
• Davis, L.K. et al. Partitioning the heritability of tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet. 9, e1003864 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium et al. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43, 969–976 (2011).
• Cross-Disorder Group of the Psychiatric Genomics Consortium et al. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).
• Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genome-wide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).
  Article PubMed Google Scholar
• Sullivan, P.F. The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 68, 182–186 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wray, N.R. et al. Genome-wide association study of major depressive disorder: new results, meta-analysis and lessons learned. Mol. Psychiatry 17, 36–48 (2012).
  Article CAS PubMed Google Scholar
• Purcell, S.M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). This is a landmark study that demonstrated a substantial contribution to risk of schizophrenia from common variation distributed throughout the genome. It also revealed evidence for genetic overlap between schizophrenia and bipolar disorder involving many common loci of small effect.
  Article CAS PubMed Google Scholar
• Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ripke, S. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson-Schmidt, H. et al. Selected rapporteur summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14–18, 2012. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 162B, 96–121 (2013).
  Article PubMed Google Scholar
• Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).
  Article CAS PubMed Google Scholar
• Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
• Sullivan, P. Don't give up on GWAS. Mol. Psychiatry 17, 2–3 (2012).
  Article CAS PubMed Google Scholar
• Morris, A.P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Plenge, R.M., Scolnick, E.M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).
  Article CAS PubMed Google Scholar
• Sanseau, P. et al. Use of genome-wide association studies for drug repositioning. Nat. Biotechnol. 30, 317–320 (2012).
  Article CAS PubMed Google Scholar
• Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).
  Article CAS PubMed Google Scholar
• Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gilman, S.R. et al. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898–907 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signaling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012).
  Article CAS PubMed Google Scholar
• Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat. Genet. 40, 880–885 (2008).
  Article CAS PubMed Google Scholar
• Williams, N.M. et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376, 1401–1408 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bergen, S.E. et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol. Psychiatry 17, 880–886 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Levinson, D.F. et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am. J. Psychiatry 168, 302–316 (2011). This is the largest meta-analysis of copy number variation in schizophrenia.
  Article PubMed PubMed Central Google Scholar
• Sanders, S.J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Vacic, V. et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499–503 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, N.M. et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am. J. Psychiatry 169, 195–204 (2012).
  Article PubMed PubMed Central Google Scholar
• Crespi, B., Stead, P. & Elliot, M. Evolution in health and medicine Sackler colloquium: comparative genomics of autism and schizophrenia. Proc. Natl. Acad. Sci. USA 107 Suppl 1, 1736–1741 (2010).
  Article PubMed PubMed Central Google Scholar
• Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011).
  Article CAS PubMed Google Scholar
• Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–99 (2012). This is the largest of four recent studies reporting the results of WES in autism families, and the only study other than Sanders et al . (2012) to use a large sample of family controls.
  Article CAS PubMed PubMed Central Google Scholar
• Neale, B.M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). This is one of four studies reporting the results of WES in autism families. Collectively, these studies have identified six brain-expressed genes harboring recurrent de novo gene-disrupting mutations that are now strong candidate genes for autism.
  Article CAS PubMed PubMed Central Google Scholar
• O'Roak, B.J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–50 (2012). This is one of four studies reporting the results of WES in autism families. The authors report recurrent gene-disrupting mutations in the CHD8 gene in unrelated probands, an observation that is highly unlikely to have occurred by chance.
  Article CAS PubMed PubMed Central Google Scholar
• Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). This study, one of four that report results from WES in autism families, used a discordant sibling family design to demonstrate an enrichment of de novo gene-disrupting mutations in autism.
  Article CAS PubMed PubMed Central Google Scholar
• Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). This is the largest WES study of de novo mutations in schizophrenia to date. The authors report an enrichment of de novo mutations in genes encoding for post-synaptic proteins.
  Article CAS PubMed PubMed Central Google Scholar
• Purcell, S. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). Together with the parallel family-based study by Fromer et al . (2014) 58 , this large case-control WES study demonstrated a burden of rare mutations in specific sets of post-synaptic genes in schizophrenia.
  Article CAS PubMed PubMed Central Google Scholar
• Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hoischen, A., Krumm, N. & Eichler, E.E. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat. Neurosci. 17, 764–772 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
  Article CAS PubMed Google Scholar
• Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012). This paper demonstrated that the majority of de novo point mutations originate in the paternal germline, and that the de novo mutation rate is positively correlated with paternal age.
  Article CAS PubMed PubMed Central Google Scholar
• Michaelson, J.J. et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431–1442 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• McGrath, J.J. et al. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry 71, 301–309 (2014).
  Article PubMed Google Scholar
• Petersen, L., Mortensen, P.B. & Pedersen, C.B. Paternal age at birth of first child and risk of schizophrenia. Am. J. Psychiatry 168, 82–88 (2011).
  Article PubMed Google Scholar
• Perrin, M.C., Brown, A.S. & Malaspina, D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr. Bull. 33, 1270–1273 (2007).
  Article PubMed PubMed Central Google Scholar
• Samocha, K.E., Robinson, E., Neale, B. & Daly, M. Statistical evaluation of de novo variation implicates a distinct etiologic subtype of autism. in XXIst World Congress of Psychiatric Genetics: Redefining Mental Illness Through Genetics (Boston, 2013).
  Google Scholar
• Liu, L. et al. Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genet. 9, e1003443 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ionita-Laza, I. et al. Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism. Proc. Natl. Acad. Sci. USA 111, 343–348 (2014).
  Article CAS PubMed Google Scholar
• Lee, S.H. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013). This paper reported evidence for overlap of common genetic variation (that is, pleiotropy) between key psychiatric disorders, including SCZ and BIP (high), SCZ and MDD (moderate), MDD and BIP (moderate), MDD and ADHD (moderate) and SCZ and ASD (low).
  Article CAS PubMed Google Scholar
• Lee, S.H. et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum. Mol. Genet. 22, 832–841 (2013).
  Article CAS PubMed Google Scholar
• Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010). This is a landmark paper that described methods for estimation of heritability for quantitative traits based on genetic relationships among individuals inferred from genome-wide data on common SNPs. Applied to height, the classic model trait for human quantitative genetics, the authors demonstrate that a substantial proportion of the heritability can be explained by many common loci throughout the genome.
  Article CAS PubMed PubMed Central Google Scholar
• 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. 88, 294–305 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, J. et al. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans. PLoS Genet. 9, e1003355 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Gratten, J., Visscher, P.M., Mowry, B.J. & Wray, N.R. Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease. Nat. Genet. 45, 234–238 (2013).
  Article CAS PubMed Google Scholar
• Visscher, P.M., Goddard, M.E., Derks, E.M. & Wray, N.R. Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. Mol. Psychiatry 17, 474–485 (2012).
  Article CAS PubMed Google Scholar
• Kapur, S., Phillips, A.G. & Insel, T.R. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol. Psychiatry 17, 1174–1179 (2012).
  Article CAS PubMed Google Scholar
• Allardyce, J., Suppes, T. & Van Os, J. Dimensions and the psychosis phenotype. Int. J. Methods Psychiatr. Res. 16 Suppl 1, S34–S40 (2007).
  Article PubMed PubMed Central Google Scholar
• Kendler, K.S. & Gardner, C.O. The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies. Psychol. Med. 27, 411–419 (1997).
  Article CAS PubMed Google Scholar
• 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 28, 2540–2542 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bromet, E.J. et al. Diagnostic shifts during the decade following first admission for psychosis. Am. J. Psychiatry 168, 1186–1194 (2011).
  Article PubMed PubMed Central Google Scholar
• Laursen, T.M., Agerbo, E. & Pedersen, C.B. Bipolar disorder, schizoaffective disorder, and schizophrenia overlap: a new comorbidity index. J. Clin. Psychiatry 70, 1432–1438 (2009).
  Article PubMed Google Scholar
• 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. 20, 668–674 (2012).
  Article PubMed PubMed Central Google Scholar
• Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, 1998).
  Google Scholar
• Ji, J. et al. Incidence of cancer in patients with schizophrenia and their first-degree relatives: a population-based study in Sweden. Schizophr. Bull. 39, 527–536 (2013).
  Article PubMed Google Scholar
• Duncan, L.E. & Keller, M.C. A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am. J. Psychiatry 168, 1041–1049 (2011).
  Article PubMed PubMed Central Google Scholar
• McGrath, J.J., Mortensen, P.B., Visscher, P.M. & Wray, N.R. Where GWAS and epidemiology meet: opportunities for the simultaneous study of genetic and environmental risk factors in schizophrenia. Schizophr. Bull. 39, 955–959 (2013).
  Article PubMed PubMed Central Google Scholar
• Medland, S.E., Jahanshad, N., Neale, B.M. & Thompson, P.M. Whole-genome analyses of whole-brain data: working within an expanded search space. Nat. Neurosci. 17, 791–800 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• WHO. The Global Burden of Disease: 2004 Update (WHO Press, 2008).
• de Candia, T.R. et al. Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. Am. J. Hum. Genet. 93, 463–470 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, L. et al. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 162B, 419–430 (2013).
  Article CAS PubMed Google Scholar
• Sullivan, P.F. The genetics of schizophrenia. PLoS Med. 2, e212 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, J., Visscher, P.M. & Wray, N.R. Sporadic cases are the norm for complex disease. Eur. J. Hum. Genet. 18, 1039–1043 (2010).
  Article PubMed Google Scholar
• Turner, M.R. et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12, 310–322 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Sebat, J., Levy, D.L. & McCarthy, S.E. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25, 528–535 (2009).
  Article CAS PubMed PubMed Central Google Scholar