Recent human genetic studies have consistently shown that mutations in the same gene or same genomic region can increase the risk of a broad range of complex neuropsychiatric disorders. Despite the steadily increasing number of examples of such nonspecific effects on risk, the underlying biological causes remain mysterious. Here we investigate the phenomenon of such nonspecific risk by identifying Mendelian disease genes that are associated with multiple diseases and explore what is known about the underlying mechanisms in these more 'simple' examples. Our analyses make clear that there are a variety of mechanisms at work, emphasizing how challenging it will be to elucidate the causes of nonspecific risk in complex disease. Ultimately, we conclude that functional approaches will be critical for explaining the causes of nonspecific risk factors discovered by human genetic studies of neuropsychiatric disorders.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes
Scientific Reports Open Access 07 December 2022
Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease
Nature Communications Open Access 07 December 2020
Genetic pleiotropy between mood disorders, metabolic, and endocrine traits in a multigenerational pedigree
Translational Psychiatry Open Access 12 October 2018
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Insel, T.R. & Landis, S.C. Twenty-five years of progress: the view from NIMH and NINDS. Neuron 80, 561–567 (2013).
Cross-Disorder Group of the Psychiatric Genomics Consoritum & Genetic Risk Outcome of Psychosis Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013). This is the first study showing that specific genetic variants are significantly associated with risk of different psychiatric disorders. By integrating genome-wide association study (GWAS) data of five different psychiatric disorders from multiple resources, this study uses statistical modeling strategies to convincingly demonstrate presence of nonspecific genetic risk factors in terms of both individual alleles and polygenic risk scores.
Ruderfer, D.M. et al. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol. Psychiatry published online, doi:10.1038/mp.2013.138 (November 26 2013).
Williams, H.J. et al. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol. Psychiatry 16, 429–441 (2011).
International Schizophrenia Consortium. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).
Cross-Disorder Group of the Psychiatric Genomics Consortium. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).
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).
Mefford, H.C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685–1699 (2008). This paper presents an excellent example of a rare, recurrent microdeletion associated with a wide spectrum of phenotypes including intellectual disability, microcephaly, cardiac abnormalities, and cataracts, emphasizing the importance of a genotype-based approach to clinical management of relevant patients.
Grayton, H.M., Fernandes, C., Rujescu, D. & Collier, D.A. Copy number variations in neurodevelopmental disorders. Prog. Neurobiol. 99, 81–91 (2012).
Bijlsma, E.K. et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur. J. Med. Genet. 52, 77–87 (2009).
Ben-Shachar, S. et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J. Med. Genet. 46, 382–388 (2009).
Morrow, E.M. Genomic copy number variation in disorders of cognitive development. J. Am. Acad. Child Adolesc. Psychiatry 49, 1091–1104 (2010).
Heinzen, E.L. et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am. J. Hum. Genet. 86, 707–718 (2010).
Ullmann, R. et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum. Mutat. 28, 674–682 (2007).
Bachmann-Gagescu, R. et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet. Med. 12, 641–647 (2010).
Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).
Digilio, M.C. et al. Congenital heart defects in recurrent reciprocal 1q21.1 deletion and duplication syndromes: rare association with pulmonary valve stenosis. Eur. J. Med. Genet. 56, 144–149 (2013).
Rosenfeld, J.A. et al. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes. Eur. J. Hum. Genet. 20, 754–761 (2012).
Kirov, G. et al. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr. Bull. 35, 851–854 (2009).
Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).
Friedman, J.I. et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol. Psychiatry 13, 261–266 (2008).
Ching, M.S. et al. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 153B, 937–947 (2010).
Gregor, A. et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med. Genet. 12, 106 (2011).
Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).
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 the first studies using a trio design to investigate the contribution of de novo mutations to a complex neuropsychiatric disorder (autism spectrum disorder, ASD). Importantly, this study establishes an analysis framework to statistically assess whether individual genes harbor significantly more de novo mutation than expected by chance. This study indicates an important, but limited, role of de novo mutations in the pathogenesis of ASD.
O′Roak, B.J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).
Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).
de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).
Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).
Epi4K Consortium. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). This is the first study that comprehensively investigates the contribution of de novo mutations to epileptic encephalopathies (EE), a spectrum of devastating neurodevelopmental disorders that can overlap with ASD and/or intellectual disability (ID) in clinical presentation. Using statistical modeling, this study clearly implicates de novo mutations as genetic risk factors of EE in both individual genes and the group of ∼4,000 genes that are most intolerant to functional genetic variation.
Sullivan, P.F., Daly, M.J. & O′Donovan, M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat. Rev. Genet. 13, 537–551 (2012). This paper provides an elegant review on genetic architectures of nine major neuropsychiatric disorders, based on discoveries from GWASs and structural variation studies.
Goldstein, D.B. et al. Sequencing studies in human genetics: design and interpretation. Nat. Rev. Genet. 14, 460–470 (2013). This paper provides an overview of implementation issues for sequencing study design, sequence data generation, variant discovery and prioritization, statistical analysis and interpretation, and functional evaluation of candidate variants along with genetic evidence to assess pathogenicity. This review introduces the idea of the 'narrative potential' inherent in sequence data and advocates for the importance of appropriate statistical criteria to secure genetic discoveries.
Stessman, H.A., Bernier, R. & Eichler, E.E. A genotype-first approach to defining the subtypes of a complex disease. Cell 156, 872–877 (2014).
McKusick, V.A. Phenotypic diversity of human diseases resulting from allelic series. Am. J. Hum. Genet. 25, 446–456 (1973).
Stearns, F.W. One hundred years of pleiotropy: a retrospective. Genetics 186, 767–773 (2010).
Mackay, T.F. Epistasis and quantitative traits: using model organisms to study gene-gene interactions. Nat. Rev. Genet. 15, 22–33 (2014).
Online Mendelian Inheritance in Man. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University http://omim.org/ (accessed 2 September 2013).
Gibbons, R.J. & Higgs, D.R. Molecular-clinical spectrum of the ATR-X syndrome. Am. J. Med. Genet. 97, 204–212 (2000).
Badens, C. et al. Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome. Clin. Genet. 70, 57–62 (2006).
Revesz, T. et al. Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol. 118, 115–130 (2009).
Heinzen, E.L. et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat. Genet. 44, 1030–1034 (2012).
Caputo, V. et al. A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. Am. J. Hum. Genet. 90, 161–169 (2012).
Le Goff, C. et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat. Genet. 44, 85–88 (2012).
Blencowe, B.J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006).
Shekarabi, M. et al. Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J. Clin. Invest. 118, 2496–2505 (2008).
Wilson, F.H. et al. Human hypertension caused by mutations in WNK kinases. Science 293, 1107–1112 (2001).
Gulsuner, S. et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013).
Willsey, A.J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).
Parikshak, N.N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013). This is one of the most successful studies mapping genes implicated by exome-based de novo mutation screens onto temporally and spatially resolved human brain transcriptomes. Notably, this study shows strong connections among the genes implicated in ASD in terms of developmental and spatial specificity, indicating involvement of specific brain circuits in the pathogenesis of ASD.
Ichinose, H. et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat. Genet. 8, 236–242 (1994).
Furukawa, Y. et al. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann. Neurol. 44, 10–16 (1998).
Koch, J. et al. Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease. J. Biol. Chem. 271, 33110–33115 (1996).
Zhou, J. et al. Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Am. J. Hum. Genet. 91, 5–14 (2012).
Otto, E.A. et al. Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). J. Med. Genet. 46, 663–670 (2009).
Mercuri, E. et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 72, 1802–1809 (2009).
Kanai, K. et al. Physicochemical property changes of amino acid residues that accompany missense mutations in SCN1A affect epilepsy phenotype severity. J. Med. Genet. 46, 671–679 (2009).
Waxman, S.G. & Dib-Hajj, S.D. Erythromelalgia: a hereditary pain syndrome enters the molecular era. Ann. Neurol. 57, 785–788 (2005).
Cox, J.J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).
de Brouwer, A.P. et al. PRPS1 mutations: four distinct syndromes and potential treatment. Am. J. Hum. Genet. 86, 506–518 (2010).
Frischmeyer, P.A. & Dietz, H.C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900 (1999).
Malan, V. et al. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am. J. Hum. Genet. 87, 189–198 (2010).
Khajavi, M. et al. Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants. Am. J. Hum. Genet. 77, 841–850 (2005).
Inoue, K. et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36, 361–369 (2004).
Nelson, D.L., Orr, H.T. & Warren, S.T. The unstable repeats–three evolving faces of neurological disease. Neuron 77, 825–843 (2013).
La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
Parvari, R. et al. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat. Genet. 32, 448–452 (2002).
Johnson, J.O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).
Tran-Viet, K.N. et al. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am. J. Hum. Genet. 92, 820–826 (2013).
Parsons, D.W. et al. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am. J. Hum. Genet. 63, 1712–1723 (1998).
Lupski, J.R., Belmont, J.W., Boerwinkle, E. & Gibbs, R.A. Clan genomics and the complex architecture of human disease. Cell 147, 32–43 (2011). This paper proposes a unified genetic model for human morbidities, highlighting the role of recent mutations. There is an instructive discussion on genetic relationships between Mendelian and complex diseases.
Nadeau, J.H. Modifier genes in mice and humans. Nat. Rev. Genet. 2, 165–174 (2001).
Wong, A.H., Gottesman, I.I. & Petronis, A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum. Mol. Genet. 14, R11–R18 (2005).
Raj, A., Rifkin, S.A., Andersen, E. & van Oudenaarden, A. Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010).
Burga, A. & Lehner, B. Beyond genotype to phenotype: why the phenotype of an individual cannot always be predicted from their genome sequence and the environment that they experience. FEBS J. 279, 3765–3775 (2012).
Tsankova, N., Renthal, W., Kumar, A. & Nestler, E.J. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 8, 355–367 (2007).
Jiang, Y.H., Bressler, J. & Beaudet, A.L. Epigenetics and human disease. Annu. Rev. Genomics Hum. Genet. 5, 479–510 (2004).
Chess, A. Random and non-random monoallelic expression. Neuropsychopharmacology 38, 55–61 (2013).
Antonellis, A. et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299 (2003).
White, J.K. et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154, 452–464 (2013).
Bilgüvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207–210 (2010). This paper demonstrates a mutation associated with a broad spectrum of malformations of cortical development that have been recognized as distinct in pathogenesis.
McCarroll, S.A. & Hyman, S.E. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron 80, 578–587 (2013).
Blair, D.R. et al. A nondegenerate code of deleterious variants in mendelian Loci contributes to complex disease risk. Cell 155, 70–80 (2013). This is the first study that systematically examines the correlation between Mendelian and complex diseases. By mining medical records over 110 million patients, the study identifies widespread comorbidity between Mendelian-Mendelian and Mendelian-complex disease pairs. The analysis also highlights the effect of genetic interactions in both Mendelian and complex diseases.
Darnell, J.C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).
Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).
Petrovski, S., Wang, Q., Heinzen, E.L., Allen, A.S. & Goldstein, D.B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709 (2013). This study provides the first comprehensive gene prioritization scoring system based on human population genetic data. The basic approach is to predict common functional variation using total variation in a regression framework, thereby identifying genes that are intolerant to functional genetic variation and therefore likely under purifying selection. The authors showed that intolerant genes are much more likely to cause neurodevelopmental disorders than tolerant genes.
Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
Zaidi, S. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013).
Girard, S.L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860–863 (2011).
Cutting, G.R. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann. NY Acad. Sci. 1214, 57–69 (2010). This paper provides an elegant review on genetic modifiers in Mendelian disorders, based on the well-studied example of cystic fibrosis.
Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
Hou, Z. et al. Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. Proc. Natl. Acad. Sci. USA 110, 15644–15649 (2013).
Spira, M.E. & Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 8, 83–94 (2013).
Venkatachalam, V. et al. Flash memory: photochemical imprinting of neuronal action potentials onto a microbial rhodopsin. J. Am. Chem. Soc. 136, 2529–2537 (2014).
The authors declare no competing financial interests.
Supplementary Table 1
Examples of genes associated with more than one Mendelian disease with literature supporting a relevant mechanism (XLSX 12 kb)
Supplementary Table 2
Schizophrenia ascertained “hot zone” de novo mutations from four schizophrenia trio sequencing studies (ref. 31, 48, 85, 89). The “hot zone” being defined as residual variation intolerance score (RVIS) ≤ 25% and variant-level PolyPhen-2 quantitative score2 ≥ 0.95 (ref. 86). (XLSX 28 kb)
- Genome-wide association study (GWAS)
A genome-wide association study (GWAS) is an unbiased screen of the genome for genetic variants that present at different frequencies in affected and unaffected individuals, that is, that associate with a phenotype. Although either rare or common variants can now be studied and analyzed for association in a genome-wide way, GWAS has historically referred to a specific, early type of genome-wide study in which a genome-wide set of common polymorphisms (single nucleotide polymorphisms) is analyzed using microarray-based technologies to find disease-associated common alleles.
Polygenic is a term meaning "many genes". A polygenic phenotype is influenced by more than one gene and can refer to common variants with small effects or rare variants with larger effects.
- Single-nucleotide polymorphism (SNP)
A single-nucleotide polymorphism (SNP) is a single base-pair position in the genome that varies between members of a species. The terms polymorphism and SNP generally refer to sequence variations that segregate in a population at an allele frequency of at least 1%.
- Copy number variation (CNV)
A common-variant association study (CVAS) is a genome-wide association study to find common variants that present at different allele frequencies in affected and unaffected individuals. The term CVAS has recently been proposed as a replacement for the term GWAS, as rare-variant association studies are also association studies and are also genome wide.
The exome is the part of a genome that encodes proteins, approximately 1% of the human genome.
- Trio family study
A trio family study is an analysis of probands and both of their parents. Sequencing-based trio studies often focus on de novo mutations that are present in the proband's genome, but are not detected in the genomes of his or her parents.
A proband is an individual being studied or reported on. The term is often used to refer to an individual affected with a disease or disorder, as distinct from their unaffected relatives.
- De novo mutation (DNM)
A de novo mutation (DNM) is a mutation that is part of an individual's genome that is not detected in the genome of either parent (although it may have arisen from a mutation in the parental germline). With the exception of de novo mutations in monozygotic twins, or those shared by siblings as a result of germline mosaicism, most new mutations are not shared by relatives and do not contribute to heritability estimates.
Pleiotropy is the phenomenon whereby a genetic variant influences variation in more than one trait or disease.
A locus is a place on a chromosome. A locus may contain one gene, multiple genes or no genes at all.
An allele is one of a number of alternative forms of a gene or locus. The minor allele is the less frequent allele at a locus and the major allele is the more frequent allele.
- Next generation sequencing (NGS)
Next generation sequencing (NGS) refers to a set of technologies that sequence DNA in massively parallel ways; for example, by optically detecting the incorporation of specific bases into millions of different DNA molecules, spatially segregated on an imageable glass surface, at the same time.
Rights and permissions
About this article
Cite this article
Zhu, X., Need, A., Petrovski, S. et al. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat Neurosci 17, 773–781 (2014). https://doi.org/10.1038/nn.3713
This article is cited by
Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes
Scientific Reports (2022)
AUTS2 isoforms control neuronal differentiation
Molecular Psychiatry (2021)
Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease
Nature Communications (2020)
Neurofibromatosis Type 1 Implicates Ras Pathways in the Genetic Architecture of Neurodevelopmental Disorders
Behavior Genetics (2020)
Psychiatric genetics and the structure of psychopathology
Molecular Psychiatry (2019)