Wednesday, 21 January 2015

Copy number intelligence

I do not write policy papers, but much to my own surprise I had written myself an imaginary policy note to cover the eventuality that I would sent a paper reporting results on the genetics of intelligence. Would I post it up, or send it round to genetics researchers for a comment? Yesterday it dawned on me, having received such a paper from a learned psychological colleague who had found it of interest, that the best policy was to post it up with minimal comment, and ask my readers to evaluate it, or send it on to colleagues who were capable of doing so.

To my untrained eye the sample sizes look far, far too small to conclude anything. However, the small samples are drawn from larger samples precisely because they are outliers in terms of brain size, so that maximises the chances of finding a result. Furthermore, they have succeeded in replicating the finding in another sample of outliers, and have asked for others to replicate the finding on the larger samples required for a proper replication.

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores
Jonathon M. Davis · Veronica B. Searles · Nathan Anderson ·Jonathon Keeney · Armin Raznahan · L. John Horwood · David M. Fergusson · Martin A. Kennedy · Jay Giedd · James M. Sikela

Hum Genet (2015) 134:67–75 DOI 10.1007/s00439-014-1489-2


DUF1220 protein domains exhibit the greatest human lineage-specific 
copy number expansion of any protein-coding sequence in the genome, 
and variation in DUF1220 copy number has been linked to both brain 
size in humans and brain evolution among primates. Given these 
findings, we examined associations between DUF1220 subtypes CON1 and 
CON2 and cognitive aptitude. We identified a linear association 
between CON2 copy number and cognitive function in two independent 
populations of European descent. In North American males, an increase 
in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 
0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, 
p = 0.003). We utilized ddPCR in a subset as a confirmatory 
measurement. This group had 26-33 copies of CON2 with a mean of 29, 
and each copy increase of CON2 was associated with a 3.3-point 
increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New 
Zealand, an increase in CON2 copy number was associated with an 
increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were 
not confounded by brain size. To our knowledge, this is the first 
study to report a replicated association between copy number of a gene 
coding sequence and cognitive aptitude. Remarkably, dosage variations 
involving DUF1220 sequences have now been linked to human brain 
expansion, autism severity and cognitive aptitude, suggesting that 
such processes may be genetically and mechanistically inter-related. 
The findings presented here warrant expanded investigations in larger, 
well-characterized cohorts.

From the methods section:

We utilized two separate populations consisting of individuals of European descent: (a) from North America and (b) from New Zealand. The North American population included unrelated non-Hispanic white individuals selected for brain size extremes through a procedure identifying residual values from a regression controlling for sex and age from a population of more than 600. This included 59 individuals (41 males and 18 females) whose ages ranged from 6 to 22. To determine reproducibility of our results, we gathered array comparative genomic hybridization (arrayCGH)-based copy number data on 75 individuals from New Zealand, 51 of whom were of European decent and selected for extremes in birth head circumference from the Christchurch Health and Development Study (Fergusson and Horwood 2001) (CHDS) cohort. The CHDS is a longitudinal study of a birth cohort of 1,265 children born in the Christchurch urban area in 1977. Participants have been examined on 23 occasions through age 35, with a focus on understanding psychosocial development, health and well-being. Cognitive measures were gathered in children aged 8–13 years in the CHDS. ArrayCGH values for CON1 and CON2 were sent to blinded statisticians to identify associations with cognitive function tests. Brain and head circumference size extremes were originally selected for association studies examining DUF1220, head circumference and brain size (Dumas et al. 2012). Although selected for size extremes, these populations were not selected for IQ metrics and IQ was normally distributed in these populations.

Can you please wave this under the nose of a population geneticist and see if you can get a response?


  1. Eternal autism-schizophrenia spectrum, hypo-mentalism ( mental efficience with less effort) and hyper-mentalism ( greater effort, i.e, some smart people can do greater effort to think).
    giftedness is a adapted or harmonized "autism and or schizophrenia ", where autism have a little advantage because predispose less mental massacre, existent in schizophrenia, but not sensorial excesses. Hypozigosis hypothesis. "autism and schizophrenia" "genes" are present in all humans. The differences between the non- full blown and full blown carriers is not "have or not" but "what is the proportion of this genes". Well, basically because diversity of genes is caused by different EXPRESSIONS them. All of us have genes responsible by cognition. Autistics have different EXPRESSIONS this genes and NOT different genes. Yes, genes are different because the different expressions or mutations.
    Autistics, functional autistics tend to be very talented, a kind of giftedness with higher custs than "normal" giftedness or as i like to say, moderate savant syndrome.


  2. Delayed gifted people, speculation, have adapted schizophrenia, when they have 20-26 years, their brain finish maturation, very similar with schizophrenia pattern.
    Precocious, prodiious OR gifted autism-like. Autistics have greater brain during childhood, while schizophrenics have opposite patterns.


  3. these effect sizes are far too large to be credible.

    1. Thanks. That was my impression: to big a load for a few genes.

  4. DUF1220 is not a gene, but a protein domain, cooperating with at least 20 genes of the NBPF gene family. During evolution DUF1220 sequences have undergone the most extreme human lineage-specific copy number expansion of any protein-coding region in the genome. The mouse has 1 copy of DUF1220, monkeys about 40 copies, chimpanzees about 120, homo sapiens nearly 300, high IQ subjects about 8 more then low IQ subjects,

    By the way, the colleague who distributed the original open letter as an email and whose name you do not mention, is himself a population geneticist.

    Until we do not have data on the segregation of DUF1220 copy numbers within families and representative population data from the Sikela lab and other labs, we will see a lot of rearguard arguing by polygeneists.

  5. Thanks for your clarifications. On your last point, I assume you mean we do need the data from the Sikela lab, but until them polygeneists will argue against this finding