Vits, SNPs and autism continued

Yet another paper from the CHARGE initiative has appeared these past few days following on from my post on the suggested link between offspring autism and maternal fever during pregnancy. The paper by Rebecca Schmidt and colleagues* overlaps to some degree with another publication last year (2011) also by Schmidt which I have lovingly titled the 'Vits & SNPs' paper given the focus on maternal supplementation just before and during pregnancy coupled with the identification of specific genetic blips (SNPs) as being potential risk factors for offspring autism.

I should warn readers that the latest paper by Schmidt et al is another autism 'risk' paper to be added to the array of past publications from this authorship group which have so far included maternal fever, maternal obesity and living next to a motorway (highway). I know some people are getting a little bit bored with seeing all these associations and the very general nature of the data being presented. Bearing that in mind, I am still a firm believer that asking questions and making such general associations is a good starting point towards forming and importantly, testing more specific hypotheses. I therefore cannot be too critical of any efforts to do this.

The recent paper summarised (bearing in mind that I'm not yet privy to the full-text of the article):

• The aim was to look at maternal folic acid intake during pregnancy and whether there was any relationship to the risk of offspring autism.
• It looks like the numbers of participants matched those of the Vits & SNPs trial** in that 429 families with children diagnosed with autism or autism spectrum disorder were included and compared against 278 control families with typically developing children (as well as 130 families with children diagnosed with a developmental delay).
• Once again, retrospective interviews were undertaken where mums were asked about their folic acid intake which were subsequently quantified. Intake did not just include actual supplements but also foods which are fortified with folic acid such as breakfast cereals. 
• The authors suggest that reported folic acid intake during the first month of pregnancy was significantly greater in mums of asymptomatic controls and a daily intake of 600 micrograms or more of folic acid was associated with a reduced risk of offspring autism during the first month of pregnancy.
• One sentence of the abstract stood out for me: "The association between folic acid and reduced ASD risk was strongest for mothers and children with [methylentetrahydrofolate reductase] MTHFR 677 C>T variant genotypes". I've read this sentence a few times and compared it with a similar statement from the previous paper by Schmidt: "Significant interaction effects were observed for maternal MTHFR 677 TT, CBS rs234715 GT + TT, and child COMT 472 AA genotypes, with greater risk for autism when mothers did not report taking prenatal vitamins periconceptionally...". What I think is being said is that mutation, in particular the MTHFR 677 C>T mutation in mums coupled with folic acid supplementation, might actually be 'protective' in some way, shape or form against offspring autism? I note that this is not the first time that the T allele has cropped up in the autism research literature bearing in mind the important effect that zygosity might have.

These are interesting findings for lots of different reasons which need to be put in perspective with regards to the methodology employed (retrospective, reliant on memories of events, etc). Folic acid supplementation during the early weeks of pregnancy is taken as standard in many countries as a protective factor against neural tube defects leading to conditions such as spina bifoda. The current guidelines (in the UK) generally suggest that 400 micrograms is the optimal daily dose (up to about 12 weeks of pregnancy). Schmidt and colleagues however report that doses above 400 micrograms (indeed quite a bit more) might be required in order to reduce the risk of offspring autism. I hasten to add that I am not providing any medical advice about this issue; just putting out a 'critically discuss this' sentence.

Folic acid, folate metabolism and autism have already come under the spotlight for quite a few different reasons. I am drawn back to the very, very interesting paper by Richard Frye and colleagues on cerebral folate receptor autoantibodies which was covered in this post, as a good example and their focus on folinic acid to potentially bypass potential issues with MTHFR (again, no medical advice or recommendation given). Combined with what is already known about with regards to MTHFR and autism, one would suspect that quite a lot more investigation would be forthcoming about the whole folate pathway and potential interference with regards to autism risk.

Accepting the need for replication and more focused study, a final implication from the latest and previous studies from Schmidt and CHARGE is the growing importance of both genes and environment potentially interacting in modifying offspring outcome with regards to autism spectrum and no doubt other conditions. We've seen this in other research; as the autocratic monarch that is genetics gives way to a more 'democratic' relationship with environmental factors, albeit variably and perhaps inconsistently from individual to individual. I'm thinking things like epigenetics also.

It is perhaps therefore apt that another modern-day monarch who's family line followed a similar path from one person on top to power to the people, celebrates a Jubilee this weekend.

God bless you, your Maj or as Sid and co put it... (but thanks for the extra Bank Holiday).

* Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. American Journal of Clinical Nutrition. May 2012.
DOI: 10.3945/​ajcn.110.004416

** Schmidt RJ. et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011; 22: 476-485.