Mys­ter­ies in di­ag­no­sis

Sci­en­tists strug­gle to find a ge­netic ba­sis for schizophre­nia

The McGill Daily - - Sci+tech - Fer­nanda Pérez Gay Juárez

Ac­cord­ing to the Cana­dian Men­tal Health As­so­ci­a­tion (CMHA) schizophre­nia af­fects ap­prox­i­mately 1 per cent of the Cana­dian pop­u­la­tion. The age of on­set is typ­i­cally dur­ing ado­les­cence or early adult­hood, and in­ci­dence of the dis­or­der does not dif­fer be­tween coun­tries. For cen­turies, the fluc­tu­at­ing men­tal state of peo­ple suf­fer­ing from schizophre­nia has re­mained a mys­tery. Un­til 1908, its name was de­men­tia pre­cox, although it has noth­ing to do with ei­ther de­men­tia or pre - con­scious­ness. It was psy­chi­a­trist Eu­gen Bleuler who coined the term schizophre­nia, from the Greek words schizein (split) and phrenos (mind). He de­scribed a wide ar­ray of men­tal func­tions as be­ing split in schizophre­nia. De­spite new in­sights and un­der­stand­ings, schizophre­nia re­mains elu­sive for re­searchers in search for a ge­netic cause.

In modern psy­chi­a­try, schizophre­nia is viewed as a con­tin­uum, and be­longs to a group of con­di­tions called psy­chotic dis­or­ders. Psy­chosis, by which psy­chotic dis­or­ders are char­ac­ter­ized, is a state in which one de­taches from re­al­ity and ex­pe­ri­ences ob­jec­tively false be­liefs (delu­sions) and al­tered per­cep­tions ( hal­lu­ci­na­tions) that one be­lieves to be the ab­so­lute truth. While go­ing through psy­chosis, most peo­ple with schizophre­nia will ex­pe­ri­ence dis­tress­ing emo­tions such as anger or un­con­trol­lable fear due to the in­ten­sity or the con­tent of psy­chosis. This can po­ten­tially lead them to en­gage in be­hav­iours they would not nor­mally do in a non-psy­chotic state. Other com­mon symp­toms are dis­or­ga­nized speech and cata­to­nia, the ap­par­ent un­re­spon­sive­ness to ex­ter­nal stim­uli and emo­tional flat­ness.

To be di­ag­nosed with schizophre­nia, the afore­men­tioned symp­toms have to be present for at least six months and cause sig­nif­i­cant dis­tress, im­pair­ing the pa­tient’s life. Due to the po­ten­tial of se­vere ef­fects on pa­tients, doc­tors and re­searchers have long ded­i­cated their ef­forts to try to find a clear cause of and thus a po­ten­tial treat­ment for schizophre­nia. So far, the only treat­ments we have are pal­lia­tive – they treat the symp­toms of psy­chosis, not schizophre­nia per se, and have many po­ten­tial ad­verse ef­fects.

Na­ture or nur­ture?

Since the term was coined, the cause of schizophre­nia has been the sub­ject of heated de­bate. Some psy­chi­a­trists in the be­gin­ning of the 20th cen­tury, such as Bleuler and Carl Jung, be­lieved there to be im­por­tant so­ci­o­log­i­cal and en­vi­ron­men­tal fac­tors, while oth­ers such as the eu­geni­cist Emil Krae­pelin thought that the cause was solely ge­netic. This con­tro­versy still ex­ists to­day, although the con­tem­po­rary neu­ro­sci­en­tific view of the dis­ease con­sid­ers both bi­o­log­i­cal and en­vi­ron­men­tal risk fac­tors. The bi­o­log­i­cal side con­sid­ers ge­net­ics to be a pre­dis­pos­ing fac­tor that, when com­bined with en­vi­ron­men­tal stresses, can trig­ger symp­toms. With ad­vances in ge­net­ics, neu­roimag­ing, and molec­u­lar pathol­ogy, to­day most sci­en­tists and psy­chi­a­trists con­sider schizophre­nia as a dis­or­der of brain devel­op­ment. Genes in­flu­ence the way our brains de­velop in utero, telling our neu­rons where and when to mi­grate to set­tle in their fi­nal spot in the cen­tral ner­vous sys­tem. Af­ter­ward, ex­ter­nal fac­tors like ob­stet­ric com­pli­ca­tions, peri­na­tal in­ci­dents, ur­ban res­i­dence, famines, and oth­ers sources of stress also con­tribute to this change in brain devel­op­ment and can af­fect our men­tal health.

Genes: where are we so far?

Ge­net­ics is a par­tic­u­larly ap­peal­ing ap­proach to dis­eases we do not un­der­stand com­pletely, be­cause it may shed light on causal bi­o­log­i­cal mech­a­nisms. Fur­ther­more, in the case of schizophre­nia, her­i­tabil­ity is a clear trait of the dis­or­der, as con­cor­dance rates of schizophre­nia for monozy­gotic twins have been found to be about 40 to 50 per cent, and her­i­tabil­ity – the prob­a­bil­ity of a child hav­ing the same con­di­tion as their par­ents – is es­ti­mated to be around 80 per cent. How­ever, the link be­tween par­tic­u­lar genes and the dis­or­der is hard to es­tab­lish given that schizophre­nia does not have any sin­gle defin­ing symp­tom or sign, and no known di­ag­nos­tic lab­o­ra­tory tests can iden­tify it so far.

Genome-wide as­so­ci­a­tion stud­ies (GWAS) – made pos­si­ble by the Hu­man Genome Project – look for mark­ers of com­mon vari­a­tion across the hu­man genome, and can com­pare peo­ple that are di­ag­nosed with the dis­or­der to those who are not. In 2014, the big­gest GWAS to date com­pared the genomes of nearly 37,000 peo­ple with schizophre­nia with more than 113,000 peo­ple with­out the dis­or­der, find­ing 128 gene vari­ants as­so­ci­ated with this con­di­tion. This study re­in­forced two ideas: the role of ge­net­ics in the devel­op­ment of schizophre­nia and the poly­genic and com­plex na­ture of this role.

GWAS do not iden­tify spe­cific genes. Rather, they pin­point big­ger ar­eas of the genome that con­tribute to risk. This kind of re­search has been use­ful in the past to de­tect causes for other com­plex dis­eases, such as di­a­betes or Crohn’s dis­ease, but the lack of bi­o­log­i­cal mark­ers for men­tal ill­ness futher com­pli­cates schizophre­nia.

Sy­napses and genes

Find­ing genes that are as­so­ci­ated with a dis­or­der does not mean that we un­der­stand how they are im­pli­cated in its devel­op­ment. Nonethe­less, this year, a team of sci­en­tists from the Broad In­sti­tute and Har­vard Med­i­cal School par­tic­i­pated in what could be a break­through in schizophre­nia genet- ics. This team found the strong­est as­so­ci­a­tion be­tween a sin­gle gene and schizophre­nia so far.

In pre­vi­ous GWAS, one of the ge­nomic re­gions as­so­ci­ated with schizophre­nia was a re­gion in our sixth chro­mo­some. Each re­gion has many genes. In this study, re­searchers de­cided to fo­cus on a sin­gle gene within this re­gion, the so-called C4 gene. In or­der to un­der­stand and cor­rob­o­rate what this gene does to our brain, the re­searchers con­ducted ge­netic ex­per­i­ments; com­par­ing what would hap­pen to mice that had this gene “blocked” (the so-called knock­out mice).

We should not for­get that the genome is like a recipe for build­ing liv­ing ma­chines: ev­ery gene codes for a pro­tein with a spe­cific func­tion. C4 cod­i­fies two pro­teins lo­cal­ized in neu­rons. These pro­teins elim­i­nate the sy­napses (neu­ral con­nec­tions) that are not needed dur­ing post­na­tal brain devel­op­ment. This process is called synap­tic prun­ing. The great­est rate of synap­tic prun­ing in hu­mans, at least in the pre­frontal cor­tex – which is im­por­tant for ex­ec­u­tive pro­cesses, judge­ment, and de­ci­sion mak­ing – hap­pens dur­ing the teenage years. Our brain con­nec­tions are con­stantly de­vel­op­ing and are crit­i­cal to be­com­ing who we are. Synap­tic prun­ing helps to elim­i­nate those con­nec­tions that are re­dun­dant or that we do not need.

The dis­cov­ery of the C4 gene ac­counts for the first time that a sin­gle gene with a spe­cific func­tion in the brain has fit the bi­o­log­i­cal the­o­ries of schizophre­nia – which fo­cus on brain devel­op­ment and mat­u­ra­tion – as well as neu­roimag­ing find­ings – which re­port neu­ral con­nec­tion pat­terns in pa­tients – and with schizophre­nia pre­sen­ta­tion – with symp­toms be­gin­ning in the late teen years. These ex­cit­ing re­sults have led to many sci­en­tific ar­ti­cles claim­ing we may be closer to ex­plain­ing schizophre­nia.

How­ever ex­cit­ing these re­sults may be, this is only one gene of the 128 that have been as­so­ci­ated with the dis­ease so far. Schizophre­nia her­i­tabil­ity is not mono­genic, but a com­plex, poly­genic dis­or­der, the bi­ol­ogy of which is far from be­ing well un­der­stood. Fur­ther­more, we should not for­get that ge­netic risk as­sesses only one side of the dis­or­der devel­op­ment model, and it hap­pens to be the one fac­tor we can­not change. At the same time that we de­velop re­search to ad­vance our bi­o­log­i­cal un­der­stand­ing of schizophre­nia, we should also study the equally com­plex char­ac­ter­is­tics of en­vi­ron­men­tal and other ex­ter­nal fac­tors in­volved. In the mean­time, work­ing on the devel­op­ment of bet­ter in­ter­ven­tion strate­gies and build­ing ed­u­ca­tion cam­paigns to re­duce stigma will as­sure a safer and more in­clu­sive en­vi­ron­ment for peo­ple liv­ing with schizophre­nia and other psy­chotic dis­or­ders.

Mind the Com­plex­i­ties is a col­umn ex­plor­ing how sci­en­tific knowl­edge can be ap­plied to the var­i­ous prob­lems with men­tal health ex­pe­ri­enced in our so­ci­ety. Fer­nanda Pérez Gay Juárez can be reached at mindthe­com­plex­i­ties@mcgill­

In 2014, the big­gest GWAS to date com­pared the genomes of nearly [150,000] peo­ple, find­ing 128 gene vari­ants as­so­ci­ated with schizophre­nia.

Maya Schade | Il­lus­tra­tor

Mind the Com­plex­i­ties

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