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Genes

Multiple genes of small effect, whose risk promoting ability is conditioned by other genes and risk factors: For this reason any positive studies are reported.

See also:- The fox and the rabbits, environmental variables and population genetics.1: Replication problems in association studies and the untapped power of GWAS. ISRN Neurology, 2011

GWAS ADCYAP1R1 AK294384 AMPD2 ATP6V1B2 ATXN7L2 BC043421 C2orf71 C3orf70 CCND2 CDH13 CDH18 CNIH4 CPM CYB561 D1SP4 DDX21 EHHADH EIF3 FAM155A FAM179A FHIT FITGB1 GDNF GNAI3 GNAT2 GRM7 GRM8 HOMER1 LAPTM4A LOC647167 LOC728275 LY86 LZTS1 NLGN1 NVL PARD3 PCLO PTPRG RORA SHC4 SLC6A15 SLC18A1 SLFN12L SP4 SYPL2 VCAN WDR26

• Glutamate DTNBP1 GRIK3 GRIK4 GRIN1 GRM3 GRM7 GRM8 HOMER1 SNAP25
• GABA GABRA3 GABRA5 GABRB3 GABRD GAD1 GAD2 PCLO
• Monoamine ADH1B ALDH2 COMT MAOA MAOB
• Dopamine DBH DDC DRD1 DRD2 DRD3 DRD4 SLC6A3
• Noradrenaline ADRA2A ADRA2C SLC6A2
• Serotonin/tryptophan/kynurenine CCBL2 HTR1A HTR1B HTR2A HTR2C HTR3A HTR3B IDO1 SLC6A4 TPH1 TPH2
• Acetlylcholine CHAT CHRNA4 CHRM2 CHRNA7 SLC5A7
• Channels CACNA1C KCNK2
• Growth factor BDNF CSF2RB EGF EMP1 FGF2 NGFR NTRK2 NTRK3 VEGF
• Oxidative stress NOS1 NOS2 NQO1 SOD2
• Myelin MYT1L
• Cytokine/immune ABCC1 CCL2 CD3E CR1 IL1B IL6 IL10 IFNG PRKCH PSMB4 PSMD9 STAT3 TBX21 TGFB1 TNF
• HPA axis GAL CRH CRHBP CRHR1 CRHR2 NR3C1 NR3C2 UCN3
• Circadian/melatonin AANAT ARNTL ASMT CLOCK CRY1 CRY2 Mir-182 NPAS2 PER2 PER3 PROKR2 RORA SIRT1 TIMELESS USP46
• Folate homocysteine FOLH1 MTHFR
• Other ABCB1 ABI3BP ACE ADA ADCY3 ADCY7 AGTR1 APAF1 APOE AR ASMT
• AVPR1B BICC1 CCKAR CNR1 CREB1 CYP1A1 CYP1B1 CYP19A1 CYP2C9 DCNP1 DGKH DISC1 DPP4 ESR1 ESR2 FAAH FADS1 FADS2 FIGN FKBP5 FOXP2 . GLDC GMIP GNAL GNB3 GPR50 GSK3B GSTT1 HMCN1 HSD11B1 .. LEP LHPP MC1R MED12 mir-30e M6PR NLGN1 NPY OPRM1 OR4B1 OXTR PACAP PAWR PCNT PDE1A PDE11A PDLIM5 PLA2G4A P2RX7 POLG PPARGC1A PRKCB PRKCG PTGS2 SAT1 SERPINE1 S100A10 S100B SIGMAR1 SLC4A10 SLC29A3 SLIT3 SULT1A1 TAAR6 TFCP2 TSNAX WFS1 XBP1 ZNF80

Genes needing KEGG mapping:NOS3 SYNE1

KEGG pathway analysis of depression genes

• Postnatal (post-partum) depression is frequent (this can also affect men, but less frequently) Reviews
  • Postnatal depression may be more severe in darker months Hiltuken et al, 2004
  • and has been associated with young age at motherhood , failure to initiate breast feeding Gagliardi et al, 2010 , urinary incontinence, and male children Sylvén et al, 2011
• Higher Toxoplasma gondii immunoglobulin G titers in infected women were related to anxiety and depression during pregnancy Groer et al, 2011.
• Depression in parents is a risk factor for depression in the offspring Ritchie and Villebrun, 2009
• Both younger (<20) and older (>50) paternal age may increase the risk of depression in the offspring Buizer-Voskamp et al, 2011 Krishnaswamy et al, 2009

• Depression is frequently observed in Hepatitis C infected patients Weinstein et al, 2011
• and in Hepatitis B infection Altindag et al, 2009
• or HIV-1 infection Bragança and Palha, 2011
• and associated with herpes simplex encephalitis Fazekas et al, 2006
• Depression has been associated with human T-cell lymphotropic virus( HTLV-1) infection Stumpf et al, 2008
• Bornavirus infection or reactivation have been linked to depression and other affective disorders Ferszt et al, 1999
  • Bornavirus related symptomatology has been reported to be improved after CSF filtration Bechter et al, 2000
• Seropositivity for influenza A, Influenza B and coronaviruses has been associated with a history of mood disorders but not with the specific diagnosis of unipolar or bipolar depression. Seropositivity for influenza B was associated with a history of suicide attempts and a history of psychotic symptoms Okusaga et al, 2011 .
• Depression has been observed in poliomyelitis survivors Kang and Lin 2011
• Chagas disease, caused by Trypanosoma Cruzi is associated with depression Ozaki et al, 2011
• Varicella Zoster cell specific immunity was lower in depressed patients and inversely correlated with the severity of depressive symptoms .
  • Depression may increase the severity of herpes zoster (shingles) Irwin et al, 2011
• Neurobrucellosis has been linked to depression Eren et al, 2006
• Nipah virus encephalitis has been associated with depression Ng et al, 2004
• Lyme disease (Borrelia infection) has ben aaaociated with depression Kaplan et al, 1999
• Suicide attempts in recurrent mood disorders have been linked to T.Gondii seropositivity Arling et al, 2009
• Sexually transmitted infections have been linked to depression Lee et al, 2009
• High salivary Lactobacillus counts have been associated with depressive symptoms Anttila et al, 1999
• Depression has been associated with tooth loss in older men Anttila et al, 2001

Social factors

• It is generally accepted that "stress" and deregulation of the hypothalamic pituitary adrenal axis are major contributory factor to depressions Refs : Stress can take many forms linked to depression and some non-exhaustive condititions include:-
  • Bereavement Childhood abuse Bullying Chronic illness Debt Divorce Homelessness Loneliness
  • Medical internship
  • Migration Sleep problems Chronic pain Trauma Work related problems menopause etc...........
• The many effects of stress are equally as diverse and are well described in Wikipedia: Stress Chronic stress This is a vast subject, not detailed here: Simple summaries include:-
  • Psychoneuroimmunology The immune-brain loop : inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion (chemical stressors) while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.
  • Fight or flight- the acute stress response
  • The Hypothalamic–pituitary–adrenal axis controls responses to stress
  • The circadian clock controls these and many other biological functions
• Inadequate housing light has been associated with depression Brown and Jacobs, 2011

Association with other diseases

• Depression has been associated with autism spectrum disorders Magnuson and Constantino, 2011
  • and with attention hyperactivity deficit disorder in the young Cole et al, 2009
• Coeliac disease has been associated with depression Addolorato et al, 2008
• Comorbid conitions include coronary heart disease Ai et al, 2010
• Depression has been associated with migraine Antonaci et al, 2011
• Depression has been asociated with the subsequent risk of developing Parkinson's disease Fang et al, 2010
• Late-life depression can be indicative of dementia or Alzheimer's disease Frisardi et al, 2011
• A biderectional relationship with epilepsy Kanner, 2011
• Associated conditions include low bone mass and central obesity Cizza. 2011
• Depression observed with carotid artery stenosis Gressier et al, 2011
• Association with Sjogren's syndrome Kang and Lin, 2010
• Depression is one of several comorbid conditions in schizophrenia Buckley et al, 2009
• Higher incidences of depression, myocardial infarction, lung cancer, diabetes and hip fracture have been reported in chronic obstructive pulmonary disease Sode et al, 2011
• Psychiatric problems including psychosis and depression are observed in Cushing syndrome (associated with high cortisol) Hirsch et al, 2000
• Depression is relatively common in systemic lupus erythematosus Meszaros et al, 2012
• Childhood-adolescence obesity has been reported as risk factor for adult depression Sanchez-Villegas et al, 2013.

Dietary and environmental factors and drugs

• Ecstasy use ( Methylenedioxymethamphetamine ) has been associated with depression Matthews and Bruno, 2010
• Vitamin B12 or Holotranscobalamin deficiency has been linked with depression Robinson et al, 2011 coupled with high levels of homocysteine Almedia et al, 2008
  • High total intakes of vitamins B-6 and B-12 may protect against depresion in the elderly Skarupski et al, 2010
• Long-term treatment of poststroke survivors with folic acid, vitamin B6, and B12 was associated with a reduction in major depression risk Almeida et al, 2010
• Diethylstilbestrol use has been associated with depression in women Kebir and Krebs, 2011
• Interferon alpha (used for hepatitis C treatment) is often associated with depression .Galvão-de Almeida et al, 2011
• Childhood depression may be associated with future smoking Niemelä et al, 2009
• Low fish consumption has been associated with severely depressed mood in men Li et al, 2011
• Air pollution has been linked to depression Szyszkowicz and Tremblay, 2011
• Serum cotinine levels ( an index of second hand smoke) has been associated with major depressive disorder, generalized anxiety disorder, attention-deficit/hyperactivity disorder, and conduct disorder Bandiera et al, 2011

Biochemistry and pathology

• Loss of white matter intergrity in the limbic system and frontal cortex related to demyelination Korgaonkar et al, 2011
• Grey matter loss in the limbic system and frontal cortex characterised by synaptic poverty Bennett, 2011
• Lower hippocampal volume Baaré et al, 2010
• Plasma levels of beta-amyloid (1-42) may predict late life depression Blasko et al, 2010
• Depression associated with low high-density lipoprotein cholesterol in women, but low low-density lipoprotein cholesterol in men Ancelin et al, 2010
• High plasma levels of lipoprotein a ( LPA ) have been reported in depression Hamidifard et al, 2009
• Increased superoxide dismutase (SOD1) and catalase activity and malondialdehyde levels in erythrocytes during depressive episodes (oxidative stress) Galecki et al, 2009
• Low whole blood glutathione peroxidase acivity Maes et al, 2011
• Reduced levels of glutathione in the prefrontal cortex Gawryluk et al, 2011
• Multiple aberrations in inflammatory, oxidative and nitic oxide related stress pathways Maes et al, 2010
• Lower levels of omega-3 polyunsaturated fatty acids in depressed patients Baghai et al, 2010
  • lower levels of eicosapentaenoic acid , docosahexaenoic acid , and total n-3 polyunsaturated fatty acids in patients with depression Lin et al, 2010
• Reduced expression of fatty acid synthesis genes in the frontal cortex in depression McNamara and Liu, 2011
• Low levels of plasma tryptophan and induction of indoleamine 2,3-dioxygenase indicative of infection/immune activation Maes, 2011
• Plasma levels of kynurenine elevated in severe depression Sublette et al, 2011 Modified ratios of kynureine to kynerenic acid have been reported in depression and other psychiatric disorders Myint , 2012
• Lower blood levels of BDNF in depressed patients Yoshimura et al, 2010
  • no plasma changes in FGF2, but an increase in VEGF Takebayashi et al, 2010
• High plasma nesfatin-1 levels have been reported in depression Ari et al, 2010
• Suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients (increased levels of IL-6 and TNF-alpha and decreased IL-2) Janelidze et al, 2011
  • Plasma aldosterone levels have also been reported to be lower in suicidal depression Hallberg et al, 2011
• Increased plasma oxytocin levels Parker et al, 2010
• Low levels of CSF S-adenosylmethionine have been reported in depression Bottiglieri et al, 1990
  • S-adenosylmethionine has been reported to possess antidepressant effects Papakostas , 2009

Depression and the immune system

• Pro-inflammatory cytokines and lipopolysacharide ( a bacterial cell wall component ) may induce depressive symptoms Maes et al, 2008.
• Depression is associated with a suppression of mitogen-induced lymphocyte proliferation and with a reduction of natural killer kell activity activity Irwin, 1999
• Depression has been frequently associated with Vitamin D deficiency Stalpers-Konijnenburg et al, 2011
  • and with lack of sunshine (needed for vitamin D synthesis)
  • See Seasonal affective disorder
• Atopy (Immunoglobulin E related allergies) can be associated with a greater risk for developing depression in women Timonen et al, 2002
• Depression and fatigue during chronic Interferon alpha treatment were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including chronic fatigue syndrome and major depression, supporting an immune contribution to these diseases Felger et al, 2011.
• An inflammatory signature (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) in lipopolysaccharide stimulated blood Spijker et al, 2010
• Autoantibodies to serotonin Maes et al, 2011
• Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by oxidative and nitrosative stress have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-L-cysteine
  • IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-L-cysteine; and the conjugated NO adducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine increased in depression Maes et al, 2011

Treatment

• Mainly serotonin (SSRI's) or varying combinations of serotonin/noradrenaline /dopamine uptake blockers, and monoamine oxidase inhibitors (see Wikipedia)
• N-acetyl cysteine (glutathione precursor) has been used as a supplement in bipolar depression Berk et al, 2008
• Supplementation with n-3 polyunsaturated fatty acids is effictive in depression treatment in elderly female patients Rondanelli et al, 2010
• Excercise may have beneficial effects in depression Trivedi et al, 2011

Geography/season and other

• Major depression has been associated with height above sea-level (possibly related to hypoxic stress) DelMastro et al, 2011
• Suicide peaks in the spring months were observed in a large Danish study Postolache et al, 2010
• Seasonal affective disorder related to latitude (greater in the north in Greenland ) Kegel et al, 2009
• Old age is a risk factor for depression and after dementia, is the most common disease in the over 65 Orzechowska et al. 2008
• Television and total media exposure in adolescence are associated with increased odds of depressive symptoms in young adulthood, especially in young men Primak et al, 2009.

Unipolar depressive disorders world map from Wikimedia commons Lokal_Profil