What is complex about complex disorders?

Rather than being polygenic, complex disorders probably represent umbrella terms for collections of conditions caused by rare, recent mutations in any of a large number of different genes.

[1]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[2]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[3]  G. Kirov,et al.  A family-based study of common polygenic variation and risk of schizophrenia , 2011, Molecular Psychiatry.

[4]  J L Rapoport,et al.  Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia , 2011, Molecular Psychiatry.

[5]  Taylor J. Maxwell,et al.  Deep resequencing reveals excess rare recent variants consistent with explosive population growth , 2010, Nature communications.

[6]  Edward Blair,et al.  Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters , 2011, American journal of medical genetics. Part A.

[7]  Shomi S. Bhattacharya,et al.  Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait , 2010, Nature Reviews Genetics.

[8]  Michel Kerszberg,et al.  Noise, delays, robustness, canalization and all that. , 2004, Current opinion in genetics & development.

[9]  Albert-László Barabási,et al.  Error and attack tolerance of complex networks , 2000, Nature.

[10]  Leslie G Biesecker,et al.  Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. , 2010, American journal of human genetics.

[11]  J. James,et al.  Frequency in relatives for an all‐or‐none trait , 1971, Annals of human genetics.

[12]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[13]  Ryan D. Hernandez,et al.  Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome , 2008, PLoS genetics.

[14]  M. King,et al.  Genomic analysis of mental illness: a changing landscape. , 2010, JAMA.

[15]  S. Maeda,et al.  Genetics of type 2 diabetes: the GWAS era and future perspectives [Review]. , 2011, Endocrine journal.

[16]  P. Visscher,et al.  Narrowing the Boundaries of the Genetic Architecture of Schizophrenia , 2009, Schizophrenia bulletin.

[17]  Kathryn Roeder,et al.  Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism , 2011, Neuron.

[18]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[19]  George A Wells,et al.  The Genome-Wide Association Study—A New Era for Common Polygenic Disorders , 2010, Journal of cardiovascular translational research.

[20]  Tom R. Gaunt,et al.  Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk , 2011, Nature.

[21]  J. Lupski,et al.  Clan Genomics and the Complex Architecture of Human Disease , 2011, Cell.

[22]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[23]  W. G. Hill,et al.  Genome partitioning of genetic variation for complex traits using common SNPs , 2011, Nature Genetics.

[24]  T. Mackay,et al.  Complex genetic architecture of Drosophila aggressive behavior , 2011, Proceedings of the National Academy of Sciences.

[25]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[26]  G. Miller,et al.  Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? , 2006, The Behavioral and brain sciences.

[27]  Joseph A. Gogos,et al.  Strong association of de novo copy number mutations with sporadic schizophrenia , 2008, Nature Genetics.

[28]  Michael R. Johnson,et al.  Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study , 2010, Brain : a journal of neurology.

[29]  Deborah L. Levy,et al.  A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay , 2010, Nature Genetics.

[30]  E. Dempster,et al.  Heritability of Threshold Characters. , 1950, Genetics.

[31]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[32]  J. Sebat,et al.  Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia , 2011, Nature.

[33]  M. Rieder,et al.  Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations , 2011, Nature Genetics.

[34]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[35]  Christian Gilissen,et al.  Unlocking Mendelian disease using exome sequencing , 2011, Genome Biology.

[36]  Qianqian Zhu,et al.  A genome-wide comparison of the functional properties of rare and common genetic variants in humans. , 2011, American journal of human genetics.

[37]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.

[38]  N. Risch,et al.  Genetic linkage and complex diseases, with special reference to psychiatric disorders , 1990, Genetic epidemiology.

[39]  David M. Evans,et al.  Genome-wide association analysis identifies 20 loci that influence adult height , 2008, Nature Genetics.

[40]  M. King,et al.  Genetic Heterogeneity in Human Disease , 2010, Cell.

[41]  C. Baker,et al.  Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. , 2008, The New England journal of medicine.

[42]  Elizabeth T. Cirulli,et al.  The Characterization of Twenty Sequenced Human Genomes , 2010, PLoS genetics.

[43]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[44]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[45]  M. Laederich,et al.  Achondroplasia: pathogenesis and implications for future treatment , 2010, Current opinion in pediatrics.

[46]  N. Risch.  Linkage strategies for genetically complex traits. I. Multilocus models. , 1990, American journal of human genetics.

[47]  J. Sebat,et al.  Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. , 2009, Trends in genetics : TIG.

[48]  R. Uher,et al.  The role of genetic variation in the causation of mental illness: an evolution-informed framework , 2009, Molecular Psychiatry.

[49]  Tanya M. Teslovich,et al.  Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index , 2010 .

[50]  P M Visscher,et al.  Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses , 2012, Molecular Psychiatry.

[51]  Christian Gilissen,et al.  A de novo paradigm for mental retardation , 2010, Nature Genetics.

[52]  Alexander R. Griffing,et al.  Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. , 2010, American journal of human genetics.

[53]  K. Majamaa,et al.  Digenic mutations in severe myoclonic epilepsy of infancy , 2009, Epilepsy Research.

[54]  Michael J. Owen,et al.  The Kraepelinian dichotomy – going, going... but still not gone , 2010, British Journal of Psychiatry.

[55]  Gabor T. Marth,et al.  Demographic history and rare allele sharing among human populations , 2011, Proceedings of the National Academy of Sciences.

[56]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[57]  S. Levy,et al.  Exome sequencing supports a de novo mutational paradigm for schizophrenia , 2011, Nature Genetics.

[58]  John Wei,et al.  Identify Risk Genes for ADHD Rare Copy Number Variation Discovery and Cross-Disorder Comparisons , 2011 .

[59]  Caleb Davis,et al.  Exome Sequencing of Ion Channel Genes Reveals Complex Profiles Confounding Personal Risk Assessment in Epilepsy , 2011, Cell.

[60]  Ulrich Stephani,et al.  Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies , 2010, PLoS genetics.

[61]  R. Gibbs,et al.  Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders , 2011, Human molecular genetics.

[62]  K. Mitchell,et al.  The Genetics of Brain Wiring: From Molecule to Mind , 2007, PLoS biology.

[63]  J A Veltman,et al.  CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy , 2008, Molecular Psychiatry.

[64]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[65]  Christopher G. Mathew,et al.  New links to the pathogenesis of Crohn disease provided by genome-wide association scans , 2008, Nature Reviews Genetics.

[66]  K. Mitchell,et al.  The genetics of neurodevelopmental disease , 2011, Current Opinion in Neurobiology.

[67]  J. Shields,et al.  A polygenic theory of schizophrenia. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[68]  K. Hemminki,et al.  The ‘Common Disease-Common Variant’ Hypothesis and Familial Risks , 2008, PloS one.

[69]  M. Daly,et al.  Genome-wide association studies for common diseases and complex traits , 2005, Nature Reviews Genetics.

[70]  David B. Goldstein,et al.  Rare Variants Create Synthetic Genome-Wide Associations , 2010, PLoS biology.

[71]  H. Chugani,et al.  Tourette syndrome is associated with recurrent exonic copy number variants , 2010, Neurology.

[72]  Q Zhao,et al.  A study of rare structural variants in schizophrenia patients and normal controls from Chinese Han population , 2008, Molecular Psychiatry.

[73]  Jianxin Shi,et al.  Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. , 2011, The American journal of psychiatry.

[74]  A. Oudenaarden,et al.  Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences , 2008, Cell.

[75]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[76]  Alexander A. Morgan,et al.  Clinical assessment incorporating a personal genome , 2010, The Lancet.

[77]  E. Zeggini,et al.  Synthetic Associations Are Unlikely to Account for Many Common Disease Genome-Wide Association Signals , 2011, PLoS biology.

[78]  O. Ohara,et al.  Mina, an Il4 repressor, controls T helper type 2 bias , 2009, Nature Immunology.

[79]  N. Katsanis,et al.  Human genetics and disease: Beyond Mendel: an evolving view of human genetic disease transmission , 2002, Nature Reviews Genetics.

[80]  A. Jackson,et al.  Mechanisms and pathways of growth failure in primordial dwarfism. , 2011, Genes & development.

[81]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[82]  O. Mayo.  The Rise and Fall of the Common Disease–Common Variant (CD–CV) Hypothesis: How the Sickle Cell Disease Paradigm Led Us All Astray (Or Did It?) , 2007, Twin Research and Human Genetics.

[83]  C. Betancur,et al.  Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting , 2011, Brain Research.

[84]  Huanming Yang,et al.  Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants , 2010, Nature Genetics.

[85]  Jing Qian,et al.  Masking epilepsy by combining two epilepsy genes , 2007, Nature Neuroscience.

[86]  H. Stefánsson,et al.  Supplementary webappendix , 2018 .

[87]  A. Zangaladze,et al.  Parieto-occipital lobe epilepsy caused by a POLG1 compound heterozygous A467T/W748S genotype , 2011, Epilepsy & Behavior.

[88]  C I Amos,et al.  Evolutionary evidence of the effect of rare variants on disease etiology , 2011, Clinical genetics.

[89]  L. Penrose,et al.  THE CORRELATION BETWEEN RELATIVES ON THE SUPPOSITION OF MENDELIAN INHERITANCE , 2022 .

[90]  Bruno van Swinderen,et al.  Flexibility in a Gene Network Affecting a Simple Behavior in Drosophila melanogaster , 2005, Genetics.

[91]  Annie E. Hill,et al.  Genetic architecture of complex traits: Large phenotypic effects and pervasive epistasis , 2008, Proceedings of the National Academy of Sciences.

[92]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.

[93]  J. Pritchard.  Are rare variants responsible for susceptibility to complex diseases? , 2001, American journal of human genetics.

[94]  D J Porteous,et al.  RETHINKING THE GENETIC ARCHITECTURE OF SCHIZOPHRENIA , 2010, Schizophrenia Research.

[95]  David B. Goldstein,et al.  The Importance of Synthetic Associations Will Only Be Resolved Empirically , 2011, PLoS biology.

[96]  Yiping Shen,et al.  Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[97]  Emily H Turner,et al.  Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes , 2009, Nature.

[98]  ’. O,et al.  Refutation of the General Single-Locus Model for the Etiology of Schizophrenia , 2022 .

[99]  L. Vissers,et al.  Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis , 2009, Journal of Medical Genetics.

[100]  Raquel E. Gur,et al.  Strong synaptic transmission impact by copy number variations in schizophrenia , 2010, Proceedings of the National Academy of Sciences.

[101]  S. Yazawa,et al.  Familial Parkinsonism with digenic parkin and PINK1 mutations , 2008, Movement disorders : official journal of the Movement Disorder Society.

[102]  David P Bick,et al.  Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease , 2011, Genetics in Medicine.

[103]  R. Fisher.  XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.

[104]  Naomi R. Wray,et al.  Synthetic Associations Created by Rare Variants Do Not Explain Most GWAS Results , 2011, PLoS biology.

[105]  Disorder Working Group.  Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 , 2012, Nature Genetics.

[106]  J. Kearney.  Genetic modifiers of neurological disease. , 2011, Current opinion in genetics & development.

[107]  Stephen W Scherer,et al.  Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. , 2010, The American journal of psychiatry.

[108]  Richard L. Abel,et al.  AIP mutation in pituitary adenomas in the 18th century and today. , 2011, The New England journal of medicine.

[109]  Paul Flicek,et al.  The functional spectrum of low-frequency coding variation , 2011, Genome Biology.

[110]  Wei Chen,et al.  Deep sequencing reveals 50 novel genes for recessive cognitive disorders , 2011, Nature.

[111]  T. Shaikh,et al.  Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes , 2010, Molecular Psychiatry.

[112]  R. Scharfmann,et al.  Molecular Diagnosis of Neonatal Diabetes Mellitus Using Next-Generation Sequencing of the Whole Exome , 2010, PloS one.

[113]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[114]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[115]  N. Hastie,et al.  Complex genetic diseases: controversy over the Croesus code , 2001, Genome Biology.

[116]  Jennifer E. Chubb,et al.  The DISC locus in psychiatric illness , 2008, Molecular Psychiatry.

[117]  C. Walsh,et al.  Allelic Diversity in Human Developmental Neurogenetics: Insights into Biology and Disease , 2010, Neuron.

[118]  Gregory M. Cooper,et al.  A Copy Number Variation Morbidity Map of Developmental Delay , 2011, Nature Genetics.

[119]  S. Lok,et al.  Increased exonic de novo mutation rate in individuals with schizophrenia , 2011, Nature Genetics.

[120]  M. Spence,et al.  Resolving genetic models for the transmission of schizophrenia , 1985, Genetic epidemiology.

[121]  Emily H Turner,et al.  Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes , 2009, Nature.

[122]  M. King,et al.  Schizophrenia: a common disease caused by multiple rare alleles , 2007, British Journal of Psychiatry.

[123]  Fassnacht,et al.  Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree , 2011, Molecular Psychiatry.

[124]  David B. Goldstein,et al.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia , 2009, PLoS genetics.

[125]  Shamil R Sunyaev,et al.  Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. , 2007, American journal of human genetics.

[126]  E. Lander,et al.  On the allelic spectrum of human disease. , 2001, Trends in genetics : TIG.

[127]  Life Technologies,et al.  A map of human genome variation from population-scale sequencing , 2011 .

[128]  Kasper Lage,et al.  Pervasive Sharing of Genetic Effects in Autoimmune Disease , 2011, PLoS genetics.

[129]  Edouard Henrion,et al.  A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing , 2011, PLoS genetics.

[130]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1962 .

[131]  Y. Kamatani,et al.  A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. , 2010, Human Molecular Genetics.