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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

ABSTRACT: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

SUBMITTER: Cross-Disorder Group of the Psychiatric Genomics Consortium

PROVIDER: S-EPMC3800159 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Lee S Hong SH Ripke Stephan S Neale Benjamin M BM Faraone Stephen V SV Purcell Shaun M SM Perlis Roy H RH Mowry Bryan J BJ Thapar Anita A Goddard Michael E ME Witte John S JS Absher Devin D Agartz Ingrid I Akil Huda H Amin Farooq F Andreassen Ole A OA Anjorin Adebayo A Anney Richard R Anttila Verneri V Arking Dan E DE Asherson Philip P Azevedo Maria H MH Backlund Lena L Badner Judith A JA Bailey Anthony J AJ Banaschewski Tobias T Barchas Jack D JD Barnes Michael R MR Barrett Thomas B TB Bass Nicholas N Battaglia Agatino A Bauer Michael M Bayés Mònica M Bellivier Frank F Bergen Sarah E SE Berrettini Wade W Betancur Catalina C Bettecken Thomas T Biederman Joseph J Binder Elisabeth B EB Black Donald W DW Blackwood Douglas H R DH Bloss Cinnamon S CS Boehnke Michael M Boomsma Dorret I DI Breen Gerome G Breuer René R Bruggeman Richard R Cormican Paul P Buccola Nancy G NG Buitelaar Jan K JK Bunney William E WE Buxbaum Joseph D JD Byerley William F WF Byrne Enda M EM Caesar Sian S Cahn Wiepke W Cantor Rita M RM Casas Miguel M Chakravarti Aravinda A Chambert Kimberly K Choudhury Khalid K Cichon Sven S Cloninger C Robert CR Collier David A DA Cook Edwin H EH Coon Hilary H Cormand Bru B Corvin Aiden A Coryell William H WH Craig David W DW Craig Ian W IW Crosbie Jennifer J Cuccaro Michael L ML Curtis David D Czamara Darina D Datta Susmita S Dawson Geraldine G Day Richard R De Geus Eco J EJ Degenhardt Franziska F Djurovic Srdjan S Donohoe Gary J GJ Doyle Alysa E AE Duan Jubao J Dudbridge Frank F Duketis Eftichia E Ebstein Richard P RP Edenberg Howard J HJ Elia Josephine J Ennis Sean S Etain Bruno B Fanous Ayman A Farmer Anne E AE Ferrier I Nicol IN Flickinger Matthew M Fombonne Eric E Foroud Tatiana T Frank Josef J Franke Barbara B Fraser Christine C Freedman Robert R Freimer Nelson B NB Freitag Christine M CM Friedl Marion M Frisén Louise L Gallagher Louise L Gejman Pablo V PV Georgieva Lyudmila L Gershon Elliot S ES Geschwind Daniel H DH Giegling Ina I Gill Michael M Gordon Scott D SD Gordon-Smith Katherine K Green Elaine K EK Greenwood Tiffany A TA Grice Dorothy E DE Gross Magdalena M Grozeva Detelina D Guan Weihua W Gurling Hugh H De Haan Lieuwe L Haines Jonathan L JL Hakonarson Hakon H Hallmayer Joachim J Hamilton Steven P SP Hamshere Marian L ML Hansen Thomas F TF Hartmann Annette M AM Hautzinger Martin M Heath Andrew C AC Henders Anjali K AK Herms Stefan S Hickie Ian B IB Hipolito Maria M Hoefels Susanne S Holmans Peter A PA Holsboer Florian F Hoogendijk Witte J WJ Hottenga Jouke-Jan JJ Hultman Christina M CM Hus Vanessa V Ingason Andrés A Ising Marcus M Jamain Stéphane S Jones Edward G EG Jones Ian I Jones Lisa L Tzeng Jung-Ying JY Kähler Anna K AK Kahn René S RS Kandaswamy Radhika R Keller Matthew C MC Kennedy James L JL Kenny Elaine E Kent Lindsey L Kim Yunjung Y Kirov George K GK Klauck Sabine M SM Klei Lambertus L Knowles James A JA Kohli Martin A MA Koller Daniel L DL Konte Bettina B Korszun Ania A Krabbendam Lydia L Krasucki Robert R Kuntsi Jonna J Kwan Phoenix P Landén Mikael M Långström Niklas N Lathrop Mark M Lawrence Jacob J Lawson William B WB Leboyer Marion M Ledbetter David H DH Lee Phil H PH Lencz Todd T Lesch Klaus-Peter KP Levinson Douglas F DF Lewis Cathryn M CM Li Jun J Lichtenstein Paul P Lieberman Jeffrey A JA Lin Dan-Yu DY Linszen Don H DH Liu Chunyu C Lohoff Falk W FW Loo Sandra K SK Lord Catherine C Lowe Jennifer K JK Lucae Susanne S MacIntyre Donald J DJ Madden Pamela A F PA Maestrini Elena E Magnusson Patrik K E PK Mahon Pamela B PB Maier Wolfgang W Malhotra Anil K AK Mane Shrikant M SM Martin Christa L CL Martin Nicholas G NG Mattheisen Manuel M Matthews Keith K Mattingsdal Morten M McCarroll Steven A SA McGhee Kevin A KA McGough James J JJ McGrath Patrick J PJ McGuffin Peter P McInnis Melvin G MG McIntosh Andrew A McKinney Rebecca R McLean Alan W AW McMahon Francis J FJ McMahon William M WM McQuillin Andrew A Medeiros Helena H Medland Sarah E SE Meier Sandra S Melle Ingrid I Meng Fan F Meyer Jobst J Middeldorp Christel M CM Middleton Lefkos L Milanova Vihra V Miranda Ana A Monaco Anthony P AP Montgomery Grant W GW Moran Jennifer L JL Moreno-De-Luca Daniel D Morken Gunnar G Morris Derek W DW Morrow Eric M EM Moskvina Valentina V Muglia Pierandrea P Mühleisen Thomas W TW Muir Walter J WJ Müller-Myhsok Bertram B Murtha Michael M Myers Richard M RM Myin-Germeys Inez I Neale Michael C MC Nelson Stan F SF Nievergelt Caroline M CM Nikolov Ivan I Nimgaonkar Vishwajit V Nolen Willem A WA Nöthen Markus M MM Nurnberger John I JI Nwulia Evaristus A EA Nyholt Dale R DR O'Dushlaine Colm C Oades Robert D RD Olincy Ann A Oliveira Guiomar G Olsen Line L Ophoff Roel A RA Osby Urban U Owen Michael J MJ Palotie Aarno A Parr Jeremy R JR Paterson Andrew D AD Pato Carlos N CN Pato Michele T MT Penninx Brenda W BW Pergadia Michele L ML Pericak-Vance Margaret A MA Pickard Benjamin S BS Pimm Jonathan J Piven Joseph J Posthuma Danielle D Potash James B JB Poustka Fritz F Propping Peter P Puri Vinay V Quested Digby J DJ Quinn Emma M EM Ramos-Quiroga Josep Antoni JA Rasmussen Henrik B HB Raychaudhuri Soumya S Rehnström Karola K Reif Andreas A Ribasés Marta M Rice John P JP Rietschel Marcella M Roeder Kathryn K Roeyers Herbert H Rossin Lizzy L Rothenberger Aribert A Rouleau Guy G Ruderfer Douglas D Rujescu Dan D Sanders Alan R AR Sanders Stephan J SJ Santangelo Susan L SL Sergeant Joseph A JA Schachar Russell R Schalling Martin M Schatzberg Alan F AF Scheftner William A WA Schellenberg Gerard D GD Scherer Stephen W SW Schork Nicholas J NJ Schulze Thomas G TG Schumacher Johannes J Schwarz Markus M Scolnick Edward E Scott Laura J LJ Shi Jianxin J Shilling Paul D PD Shyn Stanley I SI Silverman Jeremy M JM Slager Susan L SL Smalley Susan L SL Smit Johannes H JH Smith Erin N EN Sonuga-Barke Edmund J S EJ St Clair David D State Matthew M Steffens Michael M Steinhausen Hans-Christoph HC Strauss John S JS Strohmaier Jana J Stroup T Scott TS Sutcliffe James S JS Szatmari Peter P Szelinger Szabocls S Thirumalai Srinivasa S Thompson Robert C RC Todorov Alexandre A AA Tozzi Federica F Treutlein Jens J Uhr Manfred M van den Oord Edwin J C G EJ Van Grootheest Gerard G Van Os Jim J Vicente Astrid M AM Vieland Veronica J VJ Vincent John B JB Visscher Peter M PM Walsh Christopher A CA Wassink Thomas H TH Watson Stanley J SJ Weissman Myrna M MM Werge Thomas T Wienker Thomas F TF Wijsman Ellen M EM Willemsen Gonneke G Williams Nigel N Willsey A Jeremy AJ Witt Stephanie H SH Xu Wei W Young Allan H AH Yu Timothy W TW Zammit Stanley S Zandi Peter P PP Zhang Peng P Zitman Frans G FG Zöllner Sebastian S Devlin Bernie B Kelsoe John R JR Sklar Pamela P Daly Mark J MJ O'Donovan Michael C MC Craddock Nicholas N Sullivan Patrick F PF Smoller Jordan W JW Kendler Kenneth S KS Wray Naomi R NR

Nature genetics 20130811 9

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate metho ...[more]

PMID: 23933821

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Project description:ImportancePeople with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.ObjectiveTo assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them.Design, setting, and participantsUsing a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018.Main outcomes and measuresThe primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways.ResultsGenome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways.Conclusions and relevanceIn this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

Project description:BackgroundFindings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.MethodsWe analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.FindingsSNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.InterpretationOur findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.FundingNational Institute of Mental Health.

Project description:This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.

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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

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