Genetics of brain surface area and cortical thickness

The field of brain imaging has progressed remarkably during the past several years. I follow the literature because as the study of heritability of brain structure becomes more precise, it may start to be possible to study the polymorphisms that explain the genetic variation of the brain. Twin designs are the most powerful ways of assessing the heritability, although they do present certain weaknesses. A fairly comprehensive recent review of imaging studies of brain structure and heritability in twins is the paper by Peper and colleagues (2007), cited below. Most volumetric measures of the brain and its parts have heritabilities greater than 50 percent; total brain volume is about as heritable as stature in most studies, upward of 85 percent.

Fifteen years ago, the state of the art was MRI studies of a dozen or so pairs of both monozygotic and dizygotic twins. By the end of the 1990's, studies started to appear that used more than 50 of each type of twin. With sample size, the power of these studies increased. Moreover, advances in imaging technology and software began to allow researchers to focus on smaller structures, first whole lobes, and later smaller parts of the brain.

Much of your thinking happens in the cerebral cortex, which is a relatively thin layer of tissue, folded around the outside surface of the brain. Lately, MRI studies have begun to explore the structure of the cortex itself, by measuring the surface area of cortex in different regions of the brain, as well as the thickness of the cortex in the same areas.

Panizzon and colleagues (2009) examined MRIs from the Vietnam Era Twin Study of Aging, numbering 110 monozygotic and 92 dizygotic twin pairs. That sample size makes the study quite powerful for testing heritability, and they find that additive genetic (heritable) factors account for 89 percent of the variation in cortical surface area, and 81 percent of the variation in average cortical thickness. The gray matter volumes of different lobes range from 31 percent to 88 percent additive variance, with unique (non-shared) environmental factors generally accounting for a bit over half the remainder.

Despite being relatively large compared to most earlier imaging twin studies, the sample of around 200 twin pairs is still relatively weak for testing correlations among brain areas. This limitation is important to keep in mind, because one of the important genetic questions is the extent to which separate developmental modules may be involved in overall brain development. The operation of common factors across different brain regions would be evidence against extreme modularity; independence of different brain measures argues for a modular developmental model.

After controlling for brain volume, the thickness of the cortex is negatively correlated with surface area in this sample, although non-significantly so. This suggests that these two features of the cortex are relatively independent, instead of being determined by shared factors. That's after controlling for endocranial volume, however, which is strongly positively correlated with surface area. There were very few significant correlations found between different sections of the cortical surface, in either area, thickness, or volume.

The paper takes the relative independence of cortical area and thickness to be its major finding:

That surface area and thickness are genetically distinct from one another has numerous implications for continued investigations into the genetic influences of brain structure. Perhaps the most signi?cant of these is the need to explore the genetics of surface area to a greater degree. Like thickness, surface area is a highly heritable construct; yet, it has been largely overlooked in human imaging genetics research. Speci?c mutations in humans have been linked to excessive gyri?cation of the cortex as well as an increase in the cortical surface area (Piao et al. 2004; Jansen and Andermann 2005). Animal studies have also demonstrated that manipulation of speci?c genes can result in dramatic changes in arealization and expansion of select areas of the cerebral cortex like the primary visual area and the primary somatosensory area (Bishop et al. 2000; Mallamaci et al. 2000). Findings such as these would appear to suggest that the genes that in?uence surface area are critical to the early growth and development of the brain. The observed genetic relationship between total surface area and intracranial volume lends support to this conclusion. If this is the case, then a more focused examination of the genetics of surface area may produce new insights into disorders believed to have early developmental origins, such as schizophrenia (Panizzon et al. 2009: 5-6).

On one level, these kinds of studies involve incredible technology and massive investment in recruiting and following research subjects. But on another, they are very simple -- measure volumes and areas and plug them into an equation. Total brain volume is among the most heritable gross anatomical measures on the human body, and the lobar divisions of the neocortex are nearly as heritable -- while, interestingly, some smaller parts (such as the hippocampus) are apparently more influenced by unique environmental factors. Surface area and cortical thickness, despite the thin, sheet-like nature of the cortex itself, apparently go along with total brain volume with their relatively high heritabilities.


Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL, Prom-Wormley E, Neale M, Jacobson K, Lyons MJ, Grant MD, Franz CE, Xian H, Tsuang M, Fischl B, Seidman L, Dale A, Kremen WS. 2009. Distinct genetic influences on cortical surface area and cortical thickness. Cerebral Cortex (advance) doi:10.1093/cercor/bhp026

Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. 2007. Genetic influences on human brain structure: A review of brain imaging studies in twins. Human Brain Mapping 28:464-473. doi:10.1002/hbm.20398