SNPWatch: Do These Genes Make My Brain Look Big?

If you have a big head, you may be subjected to a fair bit of teasing, but science may offer you some consolation. For instance, individuals with a smaller intracranial volume (the area within the skull) are at slightly higher risk for late-life dementia. In addition, a smaller hippocampus (a section of the brain involved in learning and memory storage) has been associated with Alzheimer’s disease and mental illnesses such as depression and schizophrenia. Four papers published recently in Nature Genetics address various measures of head size and their possible health implications.

Factors influencing infant head circumference
An international team of scientists, led by H. Rob Taal from the Erasmus Medical Center in the Netherlands, has attempted to answer the question that has plagued numerous women in labor — why is my baby’s head so large?

Head size as an infant is highly heritable, meaning genetics accounts for a large portion of infant head circumference variability. To determine which genetic factors are involved, the team of researchers looked at genetic data from over 19,000 infants with European ancestry. They found that, on average, infants with the CC genotype at in the HMGA2 gene had heads that were approximately 1 mm larger around than infants with the CT genotype, and infants with the TT genotype had on average heads that were 1 mm smaller around. In addition, they found that each A at in SBNO1 gene was associated with approximately 1.2 mm larger head circumference.

Both of these SNPs are associated with height in adults. SBNO1, however, may play more of a role in neurological development; a similar gene found in fruit flies is related to development of a fly’s central nervous system.

Factors influencing intracranial volume
Early in life, brain volume and skull size are highly correlated. However, at a certain point the brain stops growing and begins to shrink while the skull remains the same size. Intracranial volume, which is the volume within the skull, is thus considered a good proxy for an individual’s maximum adult brain size.

Two of the recent Nature Genetics papers studied genetic factors influencing intracranial volume. A group of researchers led by Jason Stein from David Green School of Medicine at the University of California, Los Angeles, discovered that the SNP within the HMGA2 gene on chromosome 12 is associated with intracranial volume. The study, which used magnetic resonance imaging (MRI) to measure the skull size of over 15,000 individuals of European ancestry, suggests that the CC genotype at is associated with a 9.1 mL increase in intracranial volume over individuals with the CT genotype, and that the TT genotype was associated with a 9.1 mL decrease in intracranial volume.

Although the HMGA2 gene has been associated with height, this did not seem to fully account for the observed association between the SNP and intracranial volume. In a smaller, follow-up analysis the researchers also found that the C version of this SNP was associated with a very slight increase in IQ. But don’t “get a big head” about it if you happen to be CC at this SNP — the evidence was fairly weak and more research is needed to confirm these findings.

Another large team of researchers, led by M. Arfan Ikram, from the Erasmus Medical Center in the Netherlands, found two other SNPs influencing intracranial volume: on chromosome 6 and on chromosome 17. Each G at was associated with a 12.5 mL increase in intracranial volume, and each G at was associated with a 15 mL decrease in intracranial volume in a study of nearly 82,000 elderly individuals of European ancestry.

Factors influencing hippocampal volume
The hippocampus is a segment of the brain involved in learning and storing memories, and the size of the hippocampus has medical significance. A smaller hippocampal volume has been associated with depression, schizophrenia, and types of epilepsy. In addition, the hippocampus is often one of the first areas of the brain to be affected by Alzheimer’s disease, making it an early indicator of this disease.

A team of researchers led by Joshua C. Bis from the Department of Medicine at the University of Washington in Seattle looked at over 19,000 people with European ancestry and found that the C version at near the HRK-FBXW8 gene is associated with a 0.11 mL increase in hippocampal volume. Since the hippocampus shrinks as one ages, the authors equated this hippocampus size difference to a decrease of 3.9 years of age.

If your head is larger than most, be grateful for your possible lower risk of certain diseases and potentially higher IQ. But don’t let it go to your head — perhaps you should thank your parents for your big-head genes. Indeed, given the trouble your big noggin caused her, perhaps you should especially thank your mother this Mother’s Day!