Genetic architectures of psychiatric disorders: the emerging picture and its implications

Patrick F Sullivan, Mark J Daly, Michael O'Donovan, Patrick F Sullivan, Mark J Daly, Michael O'Donovan

Abstract

Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.

Conflict of interest statement

Conflicts of Interest

The authors report no conflicts.

Figures

Figure 1. Results pertaining to genetic architecture
Figure 1. Results pertaining to genetic architecture
(a) Plot of heritability by log10 lifetime prevalence for nine psychiatric disorders considered in this review plus three complex diseases for which genetic dissection has been particularly successful (Tables 1 and S1). Each disorder is plotted by as heritability by lifetime prevalence. Color indicates qualitative success in identifying etiological genetic variation (green=notably successful, khaki=some successes, red=minimal or no clear success to date). The bubble sizes are proportional to the numbers of cases studied in GWAS (the smaller circle indicating discovery Ncase and the larger circle the total Ncase for discovery plus replication samples). Abbreviations: ADHD=attention-deficit hyperactivity disorder, ALC=alcohol dependence, AD=Alzheimer’s disease, AN=anorexia nervosa, ASD=autism, BIP=bipolar disorder, BRCA=breast cancer, CD=Crohn’s disease, MDD=major depressive disorder, NIC=nicotine usage (maximum cigarettes per day), SCZ=schizophrenia, and T2DM=type 2 diabetes mellitus. (b) Allelic spectrum of SCZ. The inset is a conceptual schematic from a 2008 Nature Genetics review. The lower part of the figure depicts empirical results for SCZ. The x-axis is log10(AF) in controls. The y-axis is the point estimate for genotypic relative risk (GRR, log10). For clarity, confidence intervals are not shown. There are no known Mendelian variants for SCZ (AF ≪ 0.0001, GRR ≫ 50). There are no known common variants (AF > 0.05) with GRR > 1.5, and these can be excluded with > 99% statistical power. Nine SVs associated with SCZ are shown as light blue diamonds (Table 2, 1q21.1- is the deletion and 1q21.1+ is the duplication). If AF in controls was 0, AF was set to 0.0001. These SVs do not have a corresponding region in the inset. Seventeen common variants have been associated with SCZ (red circles, Table 3). SNPs contributing to the PGC SCZ risk profile score (21,171 autosomal SNPs with PT < 0.1, Box 3, panel b) are shown in light blue dots with a lowess smoother in dark blue.
Figure 1. Results pertaining to genetic architecture
Figure 1. Results pertaining to genetic architecture
(a) Plot of heritability by log10 lifetime prevalence for nine psychiatric disorders considered in this review plus three complex diseases for which genetic dissection has been particularly successful (Tables 1 and S1). Each disorder is plotted by as heritability by lifetime prevalence. Color indicates qualitative success in identifying etiological genetic variation (green=notably successful, khaki=some successes, red=minimal or no clear success to date). The bubble sizes are proportional to the numbers of cases studied in GWAS (the smaller circle indicating discovery Ncase and the larger circle the total Ncase for discovery plus replication samples). Abbreviations: ADHD=attention-deficit hyperactivity disorder, ALC=alcohol dependence, AD=Alzheimer’s disease, AN=anorexia nervosa, ASD=autism, BIP=bipolar disorder, BRCA=breast cancer, CD=Crohn’s disease, MDD=major depressive disorder, NIC=nicotine usage (maximum cigarettes per day), SCZ=schizophrenia, and T2DM=type 2 diabetes mellitus. (b) Allelic spectrum of SCZ. The inset is a conceptual schematic from a 2008 Nature Genetics review. The lower part of the figure depicts empirical results for SCZ. The x-axis is log10(AF) in controls. The y-axis is the point estimate for genotypic relative risk (GRR, log10). For clarity, confidence intervals are not shown. There are no known Mendelian variants for SCZ (AF ≪ 0.0001, GRR ≫ 50). There are no known common variants (AF > 0.05) with GRR > 1.5, and these can be excluded with > 99% statistical power. Nine SVs associated with SCZ are shown as light blue diamonds (Table 2, 1q21.1- is the deletion and 1q21.1+ is the duplication). If AF in controls was 0, AF was set to 0.0001. These SVs do not have a corresponding region in the inset. Seventeen common variants have been associated with SCZ (red circles, Table 3). SNPs contributing to the PGC SCZ risk profile score (21,171 autosomal SNPs with PT < 0.1, Box 3, panel b) are shown in light blue dots with a lowess smoother in dark blue.

References

    1. Eaton WW, et al. The burden of mental disorders. Epidemiologic reviews. 2008;30:1–14.
    1. World Health Organization. The Global Burden of Disease: 2004 Update. WHO Press; Geneva: 2008.
    1. Collins PY, et al. Grand challenges in global mental health. Nature. 2011;475:27–30.
    1. Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. American journal of public health. 2000;90:727–38.
    1. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2009. U.S. Department of Health and Human Services; Atlanta, GA: 2010.
    1. Chanock SJ, et al. Replicating genotype-phenotype associations. Nature. 2007;447:655–60.
    1. McKusick VA. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet. 2007;80:588–604.
    1. Chiurazzi P, Schwartz CE, Gecz J, Neri G. XLMR genes: update 2007. European journal of human genetics : EJHG. 2008;16:422–34.
    1. Inlow JK, Restifo LL. Molecular and comparative genetics of mental retardation. Genetics. 2004;166:835–81.
    1. McCarthy MI, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics. 2008;9:356–69.
    1. Altshuler D, Daly M. Guilt beyond a reasonable doubt. Nat Genet. 2007;39:813–5.
    1. Corvin A, Craddock N, Sullivan PF. Genome-wide association studies: a primer. Psychologal Medicine. 2010;40:1063–77.
    1. Bassett AS, Chow EW, Weksberg R. Chromosomal abnormalities and schizophrenia. Am J Med Genet. 2000;97:45–51.
    1. Vorstman JA, et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry. 2006;11:18–28.
    1. Malhotra D, Sebat J. CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics. Cell. 2012;148:1223–41.
    1. Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyping. Nature Reviews Genetics. 2011;12:363–76.
    1. Attia J, et al. How to use an article about genetic association: A: Background concepts. Jama. 2009;301:74–81.
    1. Hindorff LA, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A. 2009;106:9362–7.
    1. Pasaniuc B, et al. Extremely low-coverage sequencing enables cost effective GWAS. Nature Genetics. (In press)
    1. Ng SB, Nickerson DA, Bamshad MJ, Shendure J. Massively parallel sequencing and rare disease. Hum Mol Genet. 2010;19:R119–24.
    1. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature reviews. Genetics. 2010;11:415–25.
    1. Collins AL, et al. Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychological Medicine. 2012;42:607–16.
    1. Ng MY, et al. Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry. 2009;14:774–85.
    1. McQueen MB, et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. Am J Hum Genet. 2005;77:582–95.
    1. Trikalinos TA, et al. A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol Psychiatry. 2006;11:29–36.
    1. Zhou K, et al. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. American journal of medical genetics. Part B. 2008;147B:1392–8.
    1. Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nature Reviews Neuroscience. 2008;9:768–78.
    1. McNaughton D, et al. Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series. Neurobiology of aging. 2012;33:426, e13–21.
    1. Rovelet-Lecrux A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature genetics. 2006;38:24–6.
    1. Guerreiro RJ, et al. Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer’s disease. Neurobiology of aging. 2012;33:1008, e17–23.
    1. Pottier C, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular psychiatry. 2012
    1. Strittmatter WJ, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:1977–81.
    1. Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nature genetics. 2009;41:1088–93.
    1. Lambert JC, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nature genetics. 2009;41:1094–9.
    1. Hollingworth P, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nature genetics. 2011;43:429–35.
    1. Naj AC, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nature genetics. 2011;43:436–41.
    1. Brouwers N, et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Molecular psychiatry. 2012;17:223–33.
    1. Jones L, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PloS one. 2010;5:e13950.
    1. Guerreiro RJ, Hardy J. Alzheimer’s disease genetics: lessons to improve disease modelling. Biochemical Society transactions. 2011;39:910–6.
    1. Treusch S, et al. Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science. 2011;334:1241–5.
    1. Owen MJ, Craddock N, O’Donovan MC. Suggestion of roles for both common and rare risk variants in genome-wide studies of schizophrenia. Archives of general psychiatry. 2010;67:667–73.
    1. Itsara A, et al. Population analysis of large copy number variants and hotspots of human genetic disease. American journal of human genetics. 2009;84:148–61.
    1. Rujescu D, et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet. 2009;18:988–96.
    1. Vacic V, et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature. 2011;471:499–503.
    1. Kirov G, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Molecular psychiatry. 2011
    1. Raychaudhuri S, et al. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 2010;6
    1. Walsh T, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539–43.
    1. International Schizophrenia Consortium. Greater burden of rare copy number variants in schizophrenia. Nature. 2008;455:237–41.
    1. Sebat J, et al. Strong association of de novo copy number mutations with autism. Science. 2007
    1. Xu B, et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008
    1. Zhang D, et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry. 2009;14:376–80.
    1. Priebe L, et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Molecular psychiatry. 2011
    1. Malhotra D, et al. High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia. Neuron. 2011;72:951–63.
    1. Grozeva D, et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Archives of general psychiatry. 2010;67:318–27.
    1. McQuillin A, et al. Analysis of genetic deletions and duplications in the University College London bipolar disorder case control sample. European journal of human genetics : EJHG. 2011;19:588–92.
    1. Girard SL, et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature genetics. 2011;43:860–3.
    1. Xu B, et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nature genetics. 2011;43:864–8.
    1. Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study of schizophrenia identifies five novel loci. Nature Genetics. 2011;43:969–76.
    1. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature genetics. 2011;43:977–83.
    1. Stefansson H, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460:744–7.
    1. Zhong L, Cherry T, Bies CE, Florence MA, Gerges NZ. Neurogranin enhances synaptic strength through its interaction with calmodulin. The EMBO journal. 2009;28:3027–39.
    1. Bemis LT, et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer research. 2008;68:1362–8.
    1. Kwon E, Wang W, Tsai LH. Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. Molecular psychiatry. 2011
    1. Szulwach KE, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010;189:127–41.
    1. Smrt RD, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells. 2010;28:1060–70.
    1. Willemsen MH, et al. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. Journal of medical genetics. 2011;48:810–8.
    1. Shi Y, et al. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nature genetics. 2011;43:1224–7.
    1. Yue WH, et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature genetics. 2011;43:1228–31.
    1. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.
    1. Visscher PM, Brown MA, McCarthy MI, Yang J. Five Years of GWAS Discovery. American journal of human genetics. 2012;90:7–24.
    1. Voight BF, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42:579–89.
    1. Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–25.
    1. Houlston RS, et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nature genetics. 2010;42:973–7.
    1. Turnbull C, et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nature genetics. 2010;42:504–7.
    1. Lango Allen H, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467:832–8.
    1. Speliotes EK, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42:937–48.
    1. Stahl EA, et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nature genetics. 2012
    1. Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001;2:943–55.
    1. Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42–77.
    1. Sanders SJ, et al. Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism. Neuron. 2011;70:863–85.
    1. Pinto D, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.
    1. Marshall CR, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–88.
    1. Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012
    1. O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012
    1. Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012
    1. Wang K, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459:528–33.
    1. Weiss LA, Arking DE, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009;461:802–8.
    1. Anney R, et al. A genome-wide scan for common alleles affecting risk for autism. Human molecular genetics. 2010;19:4072–82.
    1. Ma D, et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Annals of human genetics. 2009;73:263–73.
    1. Voineagu I, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474:380–4.
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; Washington, DC: 1994.
    1. Tobacco and Genetics Consortium. Meta-analyses of genome-wide association studies implicate multiple loci for smoking behavior. Nature Genetics. 2010;42:441–7.
    1. Edenberg HJ, et al. Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcoholism, clinical and experimental research. 2010;34:840–52.
    1. Bierut LJ, et al. A genome-wide association study of alcohol dependence. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:5082–7.
    1. Kendler KS, et al. Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcoholism, clinical and experimental research. 2011;35:963–75.
    1. Heath AC, et al. A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biological psychiatry. 2011;70:513–8.
    1. Frank J, et al. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addiction biology. 2012;17:171–180.
    1. Baik I, Cho NH, Kim SH, Han BG, Shin C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. The American journal of clinical nutrition. 2011;93:809–16.
    1. Takeuchi F, et al. Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circulation journal : official journal of the Japanese Circulation Society. 2011;75:911–8.
    1. Schumann G, et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:7119–24.
    1. Bierut LJ, et al. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Molecular psychiatry. 2011
    1. Thorgeirsson TE, et al. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nature genetics. 2010;42:448–53.
    1. Liu JZ, et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature genetics. 2010;42:436–40.
    1. Saccone NL, et al. Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS genetics. 2010;6
    1. Thorgeirsson TE, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452:638–42.
    1. Truong T, et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst. 2010;102:959–71.
    1. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011;471:597–601.
    1. Major Depressive Disorder Working Group of the PGC. A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry. (In press)
    1. Rucker JJ, et al. Genome-wide association analysis of copy number variation in recurrent depressive disorder. Molecular psychiatry. 2011
    1. Caspi A, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–9.
    1. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry. 2011;68:444–54.
    1. Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Molecular psychiatry. 2010;15:18–22.
    1. Munafo MR, Durrant C, Lewis G, Flint J. Gene X environment interactions at the serotonin transporter locus. Biological psychiatry. 2009;65:211–9.
    1. Risch N, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. Jama. 2009;301:2462–71.
    1. Fergusson DM, Horwood LJ, Miller AL, Kennedy MA. Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study. The British journal of psychiatry : the journal of mental science. 2011;198:129–35.
    1. Neale BM, et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2010;49:884–97.
    1. Wang K, et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Molecular psychiatry. 2011;16:949–59.
    1. Williams NM, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010;376:1401–8.
    1. Williams NM, et al. Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3. The American journal of psychiatry. 2011
    1. Stergiakouli E, et al. Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD. The American journal of psychiatry. 2011
    1. Wray NR, Visscher PM. Narrowing the boundaries of the genetic architecture of schizophrenia. Schizophr Bull. 2010;36:14–23.
    1. McClellan J, King MC. Genomic analysis of mental illness: a changing landscape. JAMA. 2010;303:2523–4.
    1. Psychiatric GWAS Consortium. A framework for interpreting genomewide association studies of psychiatric disorders. Molecular Psychiatry. 2009;14:10–7.
    1. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8:e1000294.
    1. Wray NR, Purcell SM, Visscher PM. Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol. 2011;9:e1000579.
    1. Anderson CA, Soranzo N, Zeggini E, Barrett JC. Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol. 2011;9:e1000580.
    1. Orozco G, Barrett JC, Zeggini E. Synthetic associations in the context of genome-wide association scan signals. Hum Mol Genet. 2010;19:R137–44.
    1. Lander ES. Initial impact of the sequencing of the human genome. Nature. 2011;470:187–97.
    1. Kim Y, Zerwas S, Trace SE, Sullivan PF. Schizophrenia genetics: where next? Schizophrenia Bulletin. 2011;37:456–63.
    1. Lee S, et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genetics. 2012
    1. Davies G, et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Molecular psychiatry. 2011;16:996–1005.
    1. Yang J, et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet. 2010;42:565–9.
    1. Eichler EE, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nature reviews. Genetics. 2010;11:446–50.
    1. Hirschhorn JN. Genomewide association studies--illuminating biologic pathways. N Engl J Med. 2009;360:1699–701.
    1. Sullivan PF. Don’t give up on GWAS. Molecular Psychiatry. 2011
    1. Addington J, Heinssen R. Prediction and prevention of psychosis in youth at clinical high risk. Annual review of clinical psychology. 2012;8:269–89.
    1. Sullivan PF. Schizophrenia as a pathway disease. Nature Medicine. 2012;18:210–11.
    1. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nature reviews. Genetics. 2011;12:56–68.
    1. Miller G. Is pharma running out of brainy ideas? Science. 2010;329:502–4.
    1. Yang J, Wray NR, Visscher PM. Comparing apples and oranges: equating the power of case-control and quantitative trait association studies. Genet Epidemiol. 2010;34:254–7.
    1. Gross CP, Anderson GF, Powe NR. The relation between funding by the National Institutes of Health and the burden of disease. The New England journal of medicine. 1999;340:1881–7.
    1. Aoun S, Pennebaker D, Pascal R. To what extent is health and medical research funding associated with the burden of disease in Australia? Australian and New Zealand journal of public health. 2004;28:80–6.
    1. Gillum LA, et al. NIH disease funding levels and burden of disease. PloS one. 2011;6:e16837.
    1. Lamarre-Cliche M, Castilloux AM, LeLorier J. Association between the burden of disease and research funding by the Medical Research Council of Canada and the National Institutes of Health. A cross-sectional study. Clinical and investigative medicine. Medecine clinique et experimentale. 2001;24:83–9.
    1. Wu EQ, et al. The economic burden of schizophrenia in the United States in 2002. The Journal of clinical psychiatry. 2005;66:1122–9.
    1. Cantor RM, Lange K, Sinsheimer JS. Prioritizing GWAS results: A review of statistical methods and recommendations for their application. American journal of human genetics. 2010;86:6–22.
    1. de Bakker PI, Neale BM, Daly MJ. Meta-analysis of genome-wide association studies. Cold Spring Harbor protocols. 2010;2010 pdb top81.
    1. Psychiatric GWAS Consortium. Genome-wide association studies: history rationale and prospects for psychiatric disorders. American Journal of Psychiatry. 2009;166:540–6.
    1. Sullivan PF. The Psychiatric GWAS Consortium: big science comes to psychiatry. Neuron. 2010;68:182–6.
    1. Waters KM, et al. Consistent association of type 2 diabetes risk variants found in europeans in diverse racial and ethnic groups. PLoS genetics. 2010;6
    1. Easton DF, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447:1087–93.
    1. MacArthur DG, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012;335:823–8.
    1. Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73.
    1. Kiezun A, et al. Exome sequencing and the genetic basis of complex traits. (Submitted)
    1. de Bakker PI, et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet. 2008;17:R122–8.
    1. Ott J. Analysis of Human Genetic Linkage. The Johns Hopkins University Press; Baltimore, MD: 1999.
    1. Weiss LA, et al. Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine. 2008;358:667–75.
    1. Szatmari P, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39:319–28.
    1. Kumar RA, et al. Recurrent 16p11.2 microdeletions in autism. Human molecular genetics. 2008;17:628–38.
    1. Vassos E, et al. Penetrance for copy number variants associated with schizophrenia. Human molecular genetics. 2010;19:3477–81.
    1. Holmans P, et al. Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am J Hum Genet. 2009;85:13–24.
    1. Lee P, O’Dushlaine C, Thomas B, Purcell S. InRich: Interval-based enrichment analysis for genome-wide association studies. Bioinformatics. (In press)
    1. Rossin EJ, et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS genetics. 2011;7:e1001273.
    1. Raychaudhuri S, et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 2009;5:e1000534.
    1. Khatri P, Sirota M, Butte AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS computational biology. 2012;8:e1002375.
    1. Yaspan BL, Veatch OJ. Strategies for pathway analysis from GWAS data. Current protocols in human genetics/editorial board, Jonathan L. Haines … [et al.] 2011;Chapter 1(Unit 1):20.
    1. GO Project. The Gene Ontology: enhancements for 2011. Nucleic acids research. 2012;40:D559–64.
    1. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic acids research. 2012;40:D109–14.
    1. Mi H, et al. PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium. Nucleic acids research. 2010;38:D204–10.
    1. Croning MD, Marshall MC, McLaren P, Armstrong JD, Grant SG. G2Cdb: the Genes to Cognition database. Nucleic acids research. 2009;37:D846–51.
    1. Ruano D, et al. Functional gene group analysis reveals a role of synaptic heterotrimeric G proteins in cognitive ability. American journal of human genetics. 2010;86:113–25.
    1. Lindblad-Toh K, et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature. 2011;478:476–82.
    1. Nicolae DL, et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS genetics. 2010;6:e1000888.
    1. O’Donovan M, et al. Identification of novel schizophrenia loci by genome-wide association and follow-up. Nature Genetics. 2008;40:1053–5.
    1. Shi J, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753–7.
    1. Sklar P, et al. Whole-genome association study of bipolar disorder. Mol Psychiatry. 2008
    1. WTCCC. Genome-wide association study of 14, 000 cases of seven common diseases 3, 000 shared controls. Nature. 2007;447:661–78.
    1. Ruderfer DM, et al. A family-based study of common polygenic variation and risk of schizophrenia. Molecular psychiatry. 2011;16:887–8.
    1. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry. 2003;60:1187–92.
    1. Lichtenstein P, et al. Common genetic influences for schizophrenia and bipolar disorder: A population-based study of 2 million nuclear families. Lancet. 2009;373:234–9.
    1. Ropers HH. Genetics of early onset cognitive impairment. Annual review of genomics and human genetics. 2010;11:161–87.
    1. Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Archives of general psychiatry. 2011;68:724–31.
    1. Biederman J, Faraone SV. The effects of attention-deficit/hyperactivity disorder on employment and household income. MedGenMed : Medscape general medicine. 2006;8:12.
    1. Levinson DF, et al. Copy number variants in schizophrenia: Confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry. 2011;168:302–16.
    1. Mefford HC, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. The New England journal of medicine. 2008;359:1685–99.
    1. Stefansson H, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6.
    1. Brunetti-Pierri N, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature genetics. 2008;40:1466–71.
    1. Cooper GM, et al. A copy number variation morbidity map of developmental delay. Nature genetics. 2011;43:838–46.
    1. Mefford HC, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS genetics. 2010;6:e1000962.
    1. Jacquemont S, et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011;478:97–102.
    1. Shinawi M, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of medical genetics. 2010;47:332–41.
    1. Moreno-De-Luca D, et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. American journal of human genetics. 2010;87:618–30.
    1. Seshadri S, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–40.
    1. Cichon S, et al. Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder. Am J Hum Genet. 2011;88:372–81.
    1. Steinberg S, et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Human molecular genetics. 2011;20:4076–81.
    1. Williams HJ, et al. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry. 2010
    1. Rietschel M, et al. Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Molecular psychiatry. 2011
    1. Pe’er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32:381–385.
    1. Ferreira M, et al. Collaborative genome-wide association analysis of 10,596 individuals supports a role for Ankyrin-G (ANK3) and the alpha-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) in bipolar disorder. Nature Genetics. 2008;40:1056–8.
    1. McMahon FJ, et al. Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet. 2010;42:128–31.
    1. Breen G, et al. Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression. Nature Genetics. 2011;43:3–5.
    1. Green EK, et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Molecular psychiatry. 2010;15:1016–22.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi