Eighty new genes linked to schizophrenia

[Marco]

"This study puts psychiatry into the same category as other parts of medicine"

http://www.bbc.com/news/health-28401693

http://www.usatoday.com/story/news/nation/2014/07/21/schizophrenia-genome-immune/12947505/

I'd like to see the paper as the genes identified are linked to both neurotransmitters and the immune system supporting previous findings of peripheral systemic inflammation in 'classic psychiatric' illnesses.

 

[lansbergen]

Ditto

 

[Valentijn]

I'd like to see the paper as the genes identified are linked to both neurotransmitters and the immune system supporting previous findings of peripheral systemic inflammation in 'classic psychiatric' illnesses.

The abstract is at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13595.html but only the DRD2 gene is specifically mentioned, along with a more general references to genes related to glutamate.

 

[Valentijn]

In the .pdf with supplementary information (free, at the end of the page), they list and briefly describe the interesting genes starting at page 18: DRD2, GRM3, GRIN2A, GRIA1, SRR, CLCN3, SLC38A7, SNAT7, , RIMS1, CACNA1I, CACNA1C, CACNB2, CAMKK2, NRGN, ATP2A2, KCTD13, NLGN4X, IGSF9B, CNTN4, MEF2C, PTN, CNKSR3, PAK6, SNAP91, KCNB1, HCN1, CHRNA3, CHRNA3, CHRNA5, CHRNB4, FXR1, SATB2, FAM5B, PODXL, BCL11B, TLE1, TLE3.

SNPs are listed starting at page 23. The effect sizes (in the OR column) are mostly quite tiny, and almost all of them only reached statistical significance because the study was so huge. As an example, the SNP with the biggest effect size is rs77149735, which had an allele frequency of 2.25% in cases and 1.91% in control. Nothing earth shattering.

 

[Marco]

@Valentijn

Thanks. This on immune associations was also included in the supplementary material :

Schizophrenia associations were also strongly enriched at enhancers that are active in tissues with important immune functions, particularly B-lymphocyte lineages involved in acquired immunity (CD19 and CD20 lines, Fig. 2). These enrichments remain significant even after excluding the extended MHC region and regions containing brain enhancers (enrichment P for CD20 < 10−6), demonstrating that this finding is not an artefact of correlation between enhancer elements in different tissues and not driven by the strong and diffuse association at the extended MHC. Epidemiological studies have long hinted at a role for immune dysregulation in schizophrenia, the present findings provide genetic support for this hypothesis

(my bold)

 

[anciendaze]

I want to add my weight to what Marco has said. The strong correlation with many genes affecting immune function goes along with a great deal of prior data indicating that a portion of cases diagnosed as schizophrenia could be the result of infectious disease and/or response to same. This runs directly counter to the general idea that the problem is genetic, so we can't do much about prevention. Preventing or stopping certain infectious pathologies which are considered harmless in most of the population could save some people from a life-long nightmare of recurrent mental illness. This option has been very poorly investigated in the past, despite striking clues.

(Examples: admissions to mental hospitals following epidemics of influenza; a few solid documented successes of those forms of "pyrotherapy" which changed immune response; brief remissions and lucid behavior by schizophrenics while infected with influenza, again changing immune response; apparent cures of schizophrenia in a few patients treated very early after onset with minocycline. Concerning that last, I do not consider waiting two years reasonable to test effectiveness in cases of "recent onset." Too much work has been based on the assumption "we know this is not an infectious disease" despite known examples of infectious diseases which produce symptoms of schizophrenia, like syphilis. This last disease is also quite heritable.)

There is a different problem when SNPs which correlate with some condition turn up in genes associated with immune function, these genes are already known to be unusually variable in response to differing environments with varying pathogens. There is always the problem of catching unrelated random variation, because in biology everything is correlated with everything else. This can be predicted to become a research battleground.

I also feel the need to warn people that this is a very complex document and research collaboration, which makes it harder to analyze. Just take a look at the list of consortia involved in the supplementary notes.

 

[Snowdrop]

I often feel somewhat out of my depth these days due to increasingly poor cognitive function but always have found these things interesting.
I'm always interested to read others thoughts and insights.
I do have something to contribute that I remember reading about in the past. To do with the idea of mental illness and infectious disease as ancientdaze discussed. Children who get the chicken pox sometimes acquire OCD afterward.

 

[anciendaze]

@Snowdrop

OCD is one of many such problems. You can find reports of Tourette's syndrome, and major psychotic episodes.

 

[natasa778]

I want to add my weight to what Marco has said. The strong correlation with many genes affecting immune function goes along with a great deal of prior data indicating that a portion of cases diagnosed as schizophrenia could be the result of infectious disease and/or response to same. This runs directly counter to the general idea that the problem is genetic, so we can't do much about prevention. Preventing or stopping certain infectious pathologies which are considered harmless in most of the population could save some people from a life-long nightmare of recurrent mental illness. This option has been very poorly investigated in the past, despite striking clues.

Absolutely. Same findings in autism http://www.massgeneral.org/about/pressrelease.aspx?id=1531

...There is a different problem when SNPs which correlate with some condition turn up in genes associated with immune function, these genes are already known to be unusually variable in response to differing environments with varying pathogens. There is always the problem of catching unrelated random variation, because in biology everything is correlated with everything else. This can be predicted to become a research battleground.

Yes, very important issue that seems to be ignored in discussion parts of those 'oh we've found the risk genes' papers (guess the tactic of "ignore the problem of false positives and it will go away" is being deplored). http://scienceoveracuppa.com/2013/06/30/all-roads-once-led-to-rome-but-do-all-roads-lead-to-autism/

 

[Firestormm]

Behind the headlines. NHS Choices:
22 July 2014
Study offers insight into genetics of schizophrenia

 

[pattismith]

A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity.
2016
Abstract
CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human CaV3.3 α1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents.
Recently, two de novo missense variations, T797M and R1346H, of hCaV3.3 were identified in individuals with schizophrenia.
Here we show that R1346H, but not T797M, is associated with lower hCaV3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCaV3.3 when expressed in human cell lines compared to wild-type.
Consistent with our biochemical analyses, whole-cell hCaV3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCaV3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCaV3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons.
Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.

(I looked for the snp it is rs132572 G allele frequency is 90.89%)


Genetic risk between the CACNA1I gene and schizophrenia in Chinese Uygur population

Published: 17 July 2017

Abstract
Background
Schizophrenia (SCZ) is a common mental disorder with high heritability, and genetic factors play a major role in the pathogenesis. Recent researches indicated that the CACNA1I involved in calcium channels probably affect the potential pathogenesis of SCZ.

Results
In this study, we attempted to investigate whether the CACNA1I gene contributes the risk to SCZ in the Uighur Chinese population, and performed a case-control study involving 985 patient samples and 1218 normal controls to analyze nine SNPs within the CACNA1I gene. Among these sites, six SNPs were significantly associated with SCZ in the allele distribution: rs132575 (adjusted P allele = 0.039, OR = 1.159), rs713860 (adjusted P allele = 0.039, OR = 0.792), rs738168 (adjusted P allele = 0.039, OR = 0.785), rs136805 (adjusted P allele = 0.014, OR = 1.212), rs5757760 (adjusted P allele = 0.042, OR = 0.873) and rs5750871 (adjusted P allele = 0.039, OR = 0.859). In addition, two SNPs turned to be risk factors for SCZ not only in the allele distribution, but also in the genotype distribution: rs132575 (adjusted P genotype = 0.037) and rs136805 (adjusted P genotype = 0.037).