A critique of genetic research on schizophrenia – expensive castles in the air

In the light of the much trumpeted claims that recent research has identified genes for schizophrenia, it is important to review the track record of this type of endeavour (1). Despite thousands of studies costing millions of dollars, and endless predictions that the genetics of schizophrenia would shortly be revealed, the field has so far failed to identify any genes that substantially increase the risk of developing schizophrenia.

Following the advent of molecular genetics, some studies started to find weak associations between this or that gene and being diagnosed with schizophrenia, but attempts to replicate the findings generally failed. A large genome wide association study published in 2008, for example, analysed the distribution of 833 single nuclear polymorphisms (SNPs) in 14 genes that were thought to be the most likely ‘candidates’ for being associated with schizophrenia in a sample of 1,870 people with schizophrenia and 2002 controls. The study found no statistically significant effects for any of the genes examined and the authors concluded that ‘it is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out’ (2, p 497).

Since substantial effects were not showing up, larger samples were constructed by merging different genetic databases. These larger samples allow smaller effects to be detected. Moreover the search was broadened to include the whole genome, since early studies failed to confirm a role for ‘candidate’ genes (3).

The recent headlines were generated by a paper which reports a Genome Wide Association study in a combined sample consisting of tens of thousands of people diagnosed with schizophrenia and controls (4). Nine and a half million SNPs were examined. Out of these millions of SNPs, 128 were statistically significantly more common in people diagnosed with schizophrenia, using a ‘p’ value of 0.00001 to correct for the large number of tests conducted. These 128 SNPs were then mapped to 108 chromosomal regions or ‘loci’, most of which had never previously been thought to have anything to do with schizophrenia. The paper provides no odds ratios or other measure of the strength of the associations between the SNPs and having a schizophrenia diagnosis, but the lead researcher confirmed that each genetic loci was associated with an increase in the risk of schizophrenia of approximately 0.1% (5). Using a method dependent on multiple assumptions (Risk Profile Scores), the maximum amount of variation explained by a combination of the genes identified was 3.4% (4).

The genetics of schizophrenia parallels findings in most common physical diseases. A small number of genes with substantial effects have been identified for a small number of conditions (breast cancer, Alzheimers and AMD). Other than this, the hugely expensive human genome project and all the research that has followed from it has failed to reveal that particular genes increase the risk of developing common and important diseases to any relevant degree (6).

As in the latest schizophrenia studies, some genes appear to be slightly more common in people with conditions like Type 2 diabetes compared to those without, but having one of these genes will increase the risk of developing the disease only marginally. But the fact that people’s genetic risk varies around the average is simply tantamount to saying that everyone is different (6). We knew that anyway.

These results have lead some commentators to conclude that ‘genetic predispositions as significant factors in the prevalence of common diseases are refuted’ (6). Yet researchers and the media continue to report genetic studies as if they represent evidence that bodily diseases and behavioural or mental disorders are genetic conditions- that is conditions that are determined in an important way by detectable genetic variation. The recent schizophrenia study was reported in just such a way. ‘They’ve really managed to show that genetics plays a role’ said one schizophrenia researcher (7). The study authors claim their findings will help unravel the aetiology of the condition and lead to the development of effective and targeted drug treatments (1).

It is difficult to see that these findings will have any clinical implications for our understanding of schizophrenia or its treatment, however. Leaving aside the difficulty of defining mental abnormality or ‘schizophrenia,’ if the genes identified predict only about 0.1% of the risk, then whether you have one or two, a few or even a lot of the genes concerned tells you very little about your particular vulnerability for developing the condition.

Some commentators have concluded that the lack of evidence for a genetic contribution to common diseases shows they are fundamentally environmental conditions. Certainly we know that, in contrast to the effects of particular genes, environmental risks contribute substantially to the risk of many diseases, as well as to mental disorders, albeit in different ways. Work by biologists such as Richard Lewinton, however, shows us that many features of living beings are the result of random variation, and not predictable from either genes or environment (7).

To me, the fact that genetics contributes little to our risk of disease, or our likelihood of developing behavioural and mental disturbance, seems a matter of celebration. The idea that we are doomed by our genetic make-up to develop life-threating or disabling conditions is surely a profoundly depressing one.

We will likely never be able to fully account for why some people experience extreme mental states, but we know that poverty, unemployment, insecure attachments, familial disruption, low self-esteem, abuse etc. play a role for many. We would be better concentrating on how to eliminate these from our society if we really want to reduce the impact of mental disorder, rather that pouring more money into the bottomless pit of genetic research.

References:

1) http://online.wsj.com/articles/study-sheds-new-light-on-genes-role-in-schizophrenia-1406000363

2) Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, et al. No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 2008 Apr;165(4):497-506.

3) Collins AL, Kim Y, Sklar P, O’Donovan MC, Sullivan PF. Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med 2012 Mar;42(3):607-16. http://www.ncbi.nlm.nih.gov/pubmed/21854684

4) Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014 Jul 24;511(7510):421-7.

5) http://theconversation.com/hundreds-of-genes-and-link-to-immune-system-found-in-largest-genetic-schizophrenia-study-29531

6) http://www.independentsciencenews.org/health/the-great-dna-data-deficit/

7) Lewinton, R.C. The Doctrine of DNA: Biology as Ideology, Penguin Books, London, 1991

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9 thoughts on “A critique of genetic research on schizophrenia – expensive castles in the air

  1. Reblogged this on Beyond Meds and commented:
    Thank you Joanna Moncrieff!

    “To me, the fact that genetics contributes little to our risk of disease, or our likelihood of developing behavioural and mental disturbance, seems a matter of celebration. The idea that we are doomed by our genetic make-up to develop life-threating or disabling conditions is surely a profoundly depressing one.”

    Yes, exactly.

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