Gene linkages with IQ

A paper by Danielle Posthuma and colleagues (2005) reports on a map survey of the human genome looking for loci that may be linked to IQ. They find two significant linkages, on chromosomes 2 and 6. The data are from a large sibling and twin study, so the question is which genomic regions are shared by siblings who are similar in IQ, but different between siblings who are different in IQ.

The report is about marker linkages, not genes, so it is not clear what genes may cause the linkages they observe. The surprising thing to me is just how many possibilities there are:

Several positional candidate genes within the 2q24.1-2q31.1 linkage region have been tested for an association to autism, including GAD1 (MIM 605363), HOXD1 (MIM 142987), DLX1 (MIM 600029), DLX2 (MIM 126255), TBR-1 (MIM 604616), RAPGEF4 (MIM 606058), CHN1 (MIM 118423), SLC25A12 (MIM 603667), SCN1A (MIM 182389), SCN2A (MIM 182390), and SCN3A (MIM 182391) (Bacchelli et al. 2003; Weiss et al. 2003; Rabionet et al. 2004; Ramoz et al. 2004). Most promising as a site with possible relevance to IQ is the significant association between the relative risk to autism and two common SNPs in the mitochondrial aspartate/glutamate carrier SLC25A12 gene (Ramoz et al. 2004).
The linkage region on chromosome 6 (6p25.3-6p22.3 [D2S942D2S422]) overlaps marginally with the region 6p22.3-6p21.3 implicated in reading disability and dyslexia (Cardon et al. 1994; Fisher et al. 1999b; Gayán et al. 1999; Grigorenko et al. 2000; Kaplan et al. 2002; Willcutt et al. 2002; Deffenbacher et al. 2004). Although recently at least five candidate genes were identified that are likely to contribute to linkage with reading disability, those genes lie just outside the region defined by a drop of 1 LOD score on 6p for VIQ and FSIQ scores (Deffenbacher et al. 2004). The ALDH5A1 gene (6p22-6p23), implicated in both cognitive ability (Plomin et al. 2004) and reading disability (Deffenbacher et al. 2004), lies at the border of our 6p region.
Several genes within the 2q and 6p linkage regions have been associated with schizophrenia (NR4A2 [MIM 601828] at 2q24, DTNBP1 [MIM 607145] at 6p22, KIF13A [MIM 605433] at 6p22, and NQO2 [MIM 160998] at 6p25), fragile X syndrome (RANBP9 [MIM 603854] at 6p23), and Bardet-Biedl syndrome (BBS5 [MIM 603650] at 2q31). These disorders are accompanied by rather severe cognitive impairment, but milder variants in these same genes could influence variation in the normal range of cognitive abilities. Recently, evidence was found for linkage at 6p24 to a neurocognitive-deficit subtype of schizophrenia, in which the maximum LOD score occurred at marker D6S309, which is within the region that shows linkage to VIQ and FSIQ (Hallmayer et al., in press). Currently, dysbindin-1 (DTNBP1) at 6p22.3 is the best-supported susceptibility gene for schizophrenia (Talbot et al. 2004). Recent identification of a relationship between dysbindin-1 and hippocampal glutamate neurotransmission, a core concept of leading neurobiological theories of memory and learning, suggests further potential as an IQ gene (Talbot et al. 2004). A second positional candidate gene thought to be involved in memory processes is NRN1 (MIM 607409) at 6p25.1, which plays a role in neuritogenesis in mature brains. Naeve et al. (1997) showed that expression of neuritin, the product of NRN1, is induced by neural activity and by the activity-regulated brain-derived neurotrophic factor and neurotrophin-3. Neuritin is expressed in hippocampal and cortical neurons and is suspected to regulate neuronal plasticity during development and in the adult brain.
Given the gradual increase in heritability of IQ from childhood to late adolescence, those genes in our regions that influence brain development may be promising as candidate genes for IQ. For example, TBR-1 (MIM 604616), a neuron-specific T-box transcription factor, plays a critical role in brain development and is specifically expressed in the cortex. It is thought to be a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and may provide insights into the functions of these neurons as regulators of cortical development (Hevner et al. 2001, 2002). More specifically, Hevner et al. (2002) showed, using Tbr1 mutant mice, that Tbr1 is critical in the appropriate establishment of precise reciprocal projections between cortical areas and corresponding thalamic nuclei (Posthuma et al. 2005: 323, citations in original).

That's 22 different functional genes that might conceivably be related to cognition. Now, the implication of each of these genes is based only on the fact that somebody has found them to be worth studying in relation to cognition. But wow, that's a lot of potential on just two small segments of two chromosomes.

The question in this study is about what explains current IQ variation. I'm more interested in what may have changed in the past, which includes many things that may not be variable today.

References:

Posthuma D. et al. 2005. A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet 77:318-326. Full text online