Plexin B3 is genetically associated with verbal performance and white matter volume in human brain

Abstract

The presence of genetic influences on cognitive performance and brain volume is well established. However, specific genetic determinants of the variance of these quantitative traits are not yet known. Plexins act as receptors for semaphorins and are implicated in axon guidance, which is a key process in brain development. We have previously shown that plexin B3 is a highly potent stimulator of neurite outgrowth, which makes its gene PLXNB3 an intriguing candidate gene for traits related to human brain development and cerebral connectivity. We identified several polymorphisms in PLXNB3 predicting changes of amino acids (V598I, E1156D and V1596E) conserved at the corresponding positions of the orthologs in mouse and chimpanzee. PLXNB3 was genotyped in 303 healthy volunteers and 42 male patients with schizophrenia. Cognitive performance was measured with the vocabulary test (Wortschatztest (WST)), a method to estimate roughly general intelligence (g). Brain morphology was characterized by magnetic resonance imaging. Compared to subjects not carrying the modern, human-specific haplotype A, carriers of A scored higher in vocabulary test (WST) irrespective of diagnosis (P = 0.0004). This effect could be observed in three independent groups (healthy males: P = 0.048; schizophrenic males: P = 0.034 and healthy females: P = 0.037). Additionally, the haplotype A was associated with increased volume of brain white matter that in turn correlated with performance in the vocabulary test. These findings suggest that plexin B3 may influence cognitive performance, and the development of white matter in vivo in a way similar to its known stimulating effect on neurite outgrowth in vitro. These novel observations warrant further replication in independent samples.

Genetic foundations of human intelligence

“…But IQ and SES tend to be correlated (Deary et al 2005c;Herrnstein and Murray 1994;Higgins 1961;Jencks 1979;Korenman and Winship 2000;Waller 1971), and the extent to which and manner in which genetic influences contribute to this correlation have not been addressed. It would be surprising if genetic influences did not contribute (Hegmann and DeFries 1970;Johnson 2007), but understanding how they do contribute would help in understanding how intelligence develops and thus the biological meaning of its apparently high Rujescu et al (2007) The table is ordered according to chromosome position and split between possible candidate genes for intelligence and those improbable candidate genes for intelligence that failed replication (Lander and Kruglyak 1995) COGA collaborative study on the genetics of alcoholism heritability. Bouchard (1997) has proposed that we inherit not intellectual capacity as such; rather, species-typical affective-motivational systems shaped by the environment of evolutionary adaptation that drive both capacity and preferences.…”

Functional Genomics and Schizophrenia: Endophenotypes and Mutant Models

“…These initial observations suggest that the Semaphorin and Plexin gene families may be viable general candidates for involvement in schizophrenia, endophenotypes, or involved in related disorders. For example, PLXNA2 also has been associated with anxiety in a separate study [185], whereas variants in PLXNB3 are associated with differences in spatial memory [186].…”

Semaphorins and their Signaling Mechanisms

“…Perhaps not surprisingly, given their many roles in development and function, Semas and their related receptors have been implicated in developmental and adult onset nervous system diseases (reviewed in (12,51,119,120)), including CHARGE syndrome (121), epilepsy (122,123) schizophrenia and anxiety disorders (124–127), autism and impaired verbal performance (128), Alzheimer’s disease (AD) (129,130), Parkinson’s disease (PD) (131,132), Amyotrophic Lateral Sclerosis (ALS) (reviewed in (133)) and multiple sclerosis (MS) (reviewed (134)). While each of these diseases/disorders has a distinct etiology, it is possible that abnormal Sema expression or function could contribute to pathological changes in neuronal connectivity that are characteristic of disease including synaptic reorganization, loss of synapses or altered synaptic function.…”