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Environmental risk factors and medical conditions associated with Bipolar disorder In addition to the genes implicated in Bipolar disorder, a number of environmental risk factors including famine and viral infection have been decribed. These are listed in this table with reference links to Wikipedia and Pubmed.Ongoing clinical trails, worldwide, can be interrogated at ClinicalTrials.Gov a service of the US National Institutes of Health

Publications related to this page:

• Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability Neurochem Int. 2007 Feb;50(3):461-90..
• eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? Schizophr Bull. 2007 Nov;33(6):1343-53
• Toxoplasmosis and polygenic diseases: Extensive T.Gondii host/pathogen interactome enrichment in nine psychiatric or neurological disorders J.Pathogens, 2012

Environmental risk factors

KEGG pathway analysis of over 400 susceptibility genes

Genes from PolygenicPathways see also University of Chicago

Most should be previously referenced at these sites:- Novel genes will be linked as added.

GWAS from Genome.gov C15orf32 C15orf53 CACNA1A CACNA1C CD276 CGNL1 CTNNA2 CTSH DCTN5 DGKH DPY19L3 GRIK5 HNRNPC ITIH1 KIT LMAN2L MCTP1 MGAT4A NCAN NDUFAB1 NEK4 NF1A PALB2 PARD6B PRKAG2 PTGFR RASGRP1 SGCG SP8 ST8SIA2 SYNE1 TRANK1
Pre and non-GWAS

A2BP1 ABCA13 ABCA6 ABCB1 ABCB11 ABI3BP ABTB1 ACE ADCY8 ADCY9 ADRBK2 ADM AGT AK3L2 AKAP10 AKR1C4 AKT1 ALDH2 ALG9 ALOX12 AMTN ANK3 ANKK1 ANKRD35 AOF1 APOE AQP4 ARNTL ASMT ASTN2 ATF3 ATP1A1 ATP1A2 ATP1A3 ATP6V0D1 AVPR1B AUTS2 B3GALT5 BCL2 BCL9 BCR BDKRB2 BDNF BHLHB2 BMP6 BRCA2 BRD1 BRE BSN BTBD16 BTF3L1 C10orf120 c11orf44 C14orf143 C15orf32 C15ORF53 CABIN1 CABS1 CACNA1B CACNA1C CACNA2D1 CACNA2D4 CACNB2 CACNG5 CALCA CAMK2D CAMKK2 CAPN10 CAPN6 CCL2 CDC25B CDH12 CDH20 CDKN2A CHES1 CHMP1B CHRM2 CHRNA6 CHRNA7 CHRNB3 CIT CLOCK CMTM8 CNR2 CNTN5 CNTN6 CNTNAP2 CNTNAP5 COLEC12 COMT CPB2 CREB1 CRY2 CSF2RB CSMD1 CSNK1E CTLA4 CTNNA2 CUX2 CYP4V2 DAO DAOA DCLK1 DCTN5 DDC DDX42 DFNB31 DGCR8 DGKH DIO2 DIRAS2 DIS3L2 DISC1 DLEU2 DMTF1 DOCK3 DOCK9 DOK5 DPP10 DPP10 DPY19L3 DPYSL2 DRD1 DRD3 DSCAM DTNBP1 DUSP2 DUSP6 EDA EFNA5 EGFR EGR2 EGR3 ERBB4 ESRRG EXTL1 FABP3 FABP7 FALZ FAM109A FAM115A FAM126A FAT FAT4 FBN1 FBXO38 FGFR2 FKBP5 C11orf44 FLVCR2 FOXO3A FOXN3 FYN FZD2 G6PD GAB2 GABBR2 GABRA1 GABRA4 GABRA5 GABRB1 GABRB2 GABRB3 GABRR1 GABBR2 GAD1 GALNTL4 GASP GCHI GLT8D1 GNAZ GNB1L GNB3 GNL3 GPR109A GPR109B GPR50 GPR78 GPRASP1 GPX3 GRIA1 GRID1 GRIK4 GRIK5 GRIN1 GRIN2A GRIN2B GRM1 GRM3 GRM4 GRM7 GSK3B GSTM1 GSTT1 GUCY1B2 HCAR3 HCN4 HIP1R HK2 HMG2L1 HOXA3 HS6ST1 HS6ST3 HSD36B2 HSP90B1 HSPA4 HSPA5 HTR2A HTR2C HTR3A HTR3B HTR4 HTR5A HTR6 IFNG IGF1 IL10 IL1B IL1RN IL2RB IL6 IMPA2 INTS6 ITIH1 ITIH3 ITK JAM3 KCNJ6 KCNQ2 KCTD12 KCTD8 KIF13A KIT KLF12 KLHDC1 KLK8 KRTAP5-9 LACE1 LAMA3 LAMP3 LDB2 LLGL2 LOC283547 LOC728267 LOC730018 LRCH1 LRRC36 LRRC4C LRRC7 LY86 MAGI1 MAGI2 MAK MAOA MC5R MCHR1 MCHR2 MCM3APAS MCTP1 MCTP1 MDGA1 MLC1 MMP9 MPPE1 MTHFD1 MTHFR MTND1 MTR MUC2 MXD1 MYL12A MYL12B MYO5B N6AMT1 NALCN NALCN NAP5 NAPG NCAM1 NCAN NCAPD3 NCKAP5 NCL ND1 ND4 ND4L NDST3 NDUFAB1 NDUFV2 NEK4 NEK4 NF1A NFX1 NGL1 NOS1 NOS1AP NOS3 NPAS2 NPAS3 NR1D1 NR2E1 NR3C1 NRG1 NRXN1 NSMCE2 NTRK2 NTRK3 NXN ODZ4 OR51F2 OTX2 OXTR P2RX7 PALB2 PAX5 PAX7 PB1 PCLO PDE4B PDLIM5 PER3 PFN4 PHF17 PIK3C3 PI4KA PIP4K2A PKIA PLA2G1B PLA2R1 PLCE1 PLCG1 PLCG2 PLSCR4 POLE2 PON1 PPARD PPIL5 PPP2R2C PPP3CC PRKCZ PSKH1 PSMF1 PTGIS PTPRB PTPRE PTPRG PTPRN2 RASGRP1 RBMS3 RELN RFC3 RFX4 RGS17 RGS4 RGS5 RNPEPL1 ROR1 RORB RPGRIP1L RSRC2 RXRG RYR2 S100B SCN8A SDC2 SEMG2 SGCD SHOC2 SIGLEC6 SKIV2L SLC12A6 SLC18A1 SLC18A2 SLC22A16 SLC25A4 SLC26A7 SLC39A3 SLC6A4 SLIT3 SLITRK2 LOC100507206 (Slynar) SNAP25 SNX27 SOD2 SORCS2 SOX5 SP4 SP8 SPR SPTLC3 SRP54 SST SSTR5 ST3GAL1 ST8SIA2 STAB1 SUPT4H1 SVEP1 SYBL1 SYK SYN3 SYNE1 SYNGR1 SYNJ1 TAAR6 TACR1 TCF4 TCF7L1 TDO2 TDP1 TDRD9 TEC TH THOC1 THRB THSD7A TIMELESS TLE4 TMEM108 TNF TOM1 TP53I3 TPH2 TRDN TRPM2 TSHZ2 TSNAX TSPAN8 TUBA8 VAPA VAV3 VIP VPRBP WDFY2 WFS1 WNT2B WNT7A XBP1 XRCC1 YWHAH ZADH1 ZBTB44 ZNF274 ZNF284 ZNF490 ZNF659 ZNF678 ZNF804A

To be mapped in KEGG pathways DCLK1 NFIA SEZ6L NRG3 HTR1A GRN . SLC2A2 TGM2 PDE10A VDR IFT27 CACNG2 YWHAE . PLCB1 ITGA9 PLA2G6 . PRSS35 SNAP91 NUMB SLC1A1 GSTZ1 DBH

Epigenetics:

Methylated genes Gene methlylation provides a potential link with environmental factors

COMT HCG9 HTR1A HTR2A PPIEL SLC12A6

Prenatal and perinatal

• Maternal Famine as a risk factor for offspring Brown et al, 2000
• Low birthweight for pre-term births can be a risk factor in later life Laursen et al, 2007
• Diverse perinatal risk factors (drugs and birth complications) can increase the risk of pediatric bipolar disorderPavuluri et al, 2006
• Prenatal infection during the first trimester (Influenza or common cold) have been associated with subsequent cycloid psychosis in the offspring Stober et al, 1997
• A significant, increase in the risk of Bipolar disorder in the offspring after exposure to maternal influenza at any time during pregnancy (odds ratio = 3.82) Parboosing et al, 2013.
• An excess of winter/spring births has been observed for Bipolar disorder and schizophrenia Torrey et al, 1997
• Maternal stress during the first trimester (Arab-Israeli War) associated with an increased risk of bipolar disorder and other affective disorders in the offspring Kleinhaus et al, 2013

• Less parental warmth, affection, and intimacy, and more quarreling and forceful punishment. are associated with pediatric bipolar disorder . Schenkel et al, 2008
• Early childhood stress (Maternal loss): Major childhood adversity. Mortensen et al, 2003

• Borna Virus infection Fu et al, 1993
• Herpes simplex (HSV-1) infection Dickerson et al, 2004 acting in synergy with possessioin of a COMT risk gene Dickerson et al, 2006
  • HSV-1 modifies executive function in bipolar patients Gerber et al, 2011
• Hepatitis C infection El Serag et al, 2002 alone or in combination with interferon therapy Sockalingam et al, 2007
  • Liver disease (viral or cirrhotic) is common in bipolar disorder and schizophrenia Fuller et al, 2011
• HIV infection Cruess et al, 2003
• Seropositivity for influenza B and coronaviruses were associated with a history of affective disorders Okusaga et al, 2010
• Increased incidence of Bipolar disorder and other psychiatric conditions in prison population with HIV, HIV/Hepatitis B or HIV/ Hepatitis C infections Baillargeon et al, 2008
• Retroviral DNA (HERV-K10) Frank et al, 2005
• Mania and psychosis induced by influenza infection Steinberg et al, 1972
• Leptospirosis can present with mania and psychosis Semiz et al, 2005
• Lyme disease (Borrelia burgdorferri infection) Fallon and Nields, 1994
• Mania and psychosis induced by therapy against H.Pylori Neff and Kuo, 2002
• Personality disorders, including bipolar disorder have been associated with Toxoplasma Gondii infection Hinze-Selch et al, 2010
  • For bipolar disorder see Hamdani et al, 2012
• Mania has been associated with Dengue virus infection Mendhekar et al, 2006
• and reported after cryptococcal meningitis Johnson and Naraqi 1993
• Simian cytomegalovirus-related stealth virus has been found in the cerebrospinal fluid of a patient with bipolar psychosis and acute encephalopathy Martin, 1996.
• Seropositivity for influenza A influenza B and coronaviruses were associated with a history of mood disorders but not with the specific diagnosis of unipolar or bipolar depression Okusaga et al, 2011
• Retroviral HERV-W env transcription elevated in bipolar disorder and schizophrenia Perron et al, 2013

• Hypothyroidism .Thomsen et al, 2005
• Autoimmune thyroiditis . Vonk et al, 2007
• Correlation of allergy to depressive symptoms (tree pollen) Postolache et al, 2007
• Corticosteroid use can be associated with a range of psychiatric disorders including mania, depression and psychosis Cerullo, 2008
• Interferon therapy Greenberg et al, 2000. Raison et al, 2005
• High prevalence of erythrocyte antigens Weir-Medina et al, 2002
• Antibodies to TPO, H/K ATPase, and GAD65.Padmos et al, 2004
• Increased levels of antibodies to gliadin Dickerson et al, 2011
• Increased immune activation by casein dietary antigens Severance et al, 2010
• High levels of activated T cells Breunis et al, 2003
• Activated monocytes and T cells Drexhage et al, 2011

• Anorexia Nervosa and eating disorders .Wildes et al, 2007 .Javaras et al, 2008 .McElroy et al, 2006
• Association with with adult attention deficit hyperactivity disorder (ADHD)Tamam et al, 2008
• Association with with fibromyalgia Arnold et al, 2006
• Association with the metabolic syndrome and diabetesVan Winkel et al, 2008
• Prevalence of obesity in drug naive patients Maina et al,2008
• Associated with increased cancer risk BarChana et al, 2008
• Individuals with epilepsy, multiple sclerosis, migraine and circulatory disorders may have a higher prevalence of bipolar disorder McIntyre et al, 2007
• Prior depression increases the risk of subsequently developing bipolar disorder Gilman et al, 2012
• Association with liver diseases, including hepatitis C and alcohol-related cirrhosis Fuller et al, 2011

• An urban environment can contribute to the psychosis aspects of Bipolar disorder Kaymaz et al, 2006
• Urban environment Kaymaz et al, 2006
• Relatively high prevalence of substance and alcohol abuse Sherazi et al, 2006
• Excessive cannabis use has been associatyed with an earlier age at onset Lagerberg et al, 2011
• Pesticides and disease database

• Elevated daytime cortisol levels in late adolescence may be a risk factor for subsequent affective disorders Ellenbogen et al, 2011.
• Hypovitaminosis (Vitamin D) is associated with bipolar disorder Cherniak et al, 2009
• Elevated homocysteine levels have been associated with bipolar disorder Dias et al, 2009
• Glutathione depletion is common in bipolar and many other disorders. Precursor treatment with N-acetyl cysteine has been reported to be effective in bipolar disorder Magalhães et al, 2011
• Deficits in erythrocyte docosahexaenoic acid composition McNamara et al, 2010
• Disruption of circadian rhythms associated with Bipolar disorder LeStrat et al, 1998
• Mania admissions are higher in winter and lower in summer Volpe and Delporto, 2006
• Mania has been reported following Vitamin B12 deficiency Goggans, 1984
• Negative association with fish consumption Noaghiul and Hibbeln, 2003
• Long-chain omega-3 polyunsaturated fatty acid deficiency is a feature of depression and bipolar disorder McNamara, 2011
• Consanguinity (inbreeding) has been asociated with both Bipolar disorder and schizophrenia Mansour et al, 2009
• Agmatinase, which metabolises an endogenous antidepressant, agmatine, is upregulated in patients with mood disorders Bernstein et al, 2011
• High levels of lead in hair samples have been noted in bipolar disorder Kanofsky et al, 1986
• High levels of vanadium in hair samples have ben noted Naylor et al, 1984

The disability map for Bipolar disorder in 2002: From Wikimedia commons