Recent adaptive selection at MAOB and ancestral susceptibility to schizophrenia

Abstract

The ancestral susceptibility hypothesis has been proposed to explain the existence of susceptibility alleles to common diseases. Some ancestral alleles, reflecting ancient adaptations, may be poorly adapted to the more contemporary environmental conditions giving rise to an increased risk to suffer some common disorders. In order to test this hypothesis in schizophrenia, we focused on the monoamine oxidase B gene (MAOB). This gene is involved in deamination of several monoamines, including both xenobiotic amines present in several foods, as well as neurotransmitters such as dopamine. In addition, preliminary analysis based on phase I HapMap data suggested that recent natural selection has acted on this locus. We further explored the existence of this recent positive selection using a test based on extension of linkage disequilibrium (LD) to large distance at the specific selected haplotype taking data from HapMap phase II, and searched for association of the ancestral haplotypes with schizophrenia in a sample of 532 schizophrenic patients and 597 controls from Spain. Our analysis suggested the existence of a haplotype of MAOB subject to recent selection. In agreement with the ancestral susceptibility hypothesis, the ancestral haplotypes were significantly over-represented in patients (P = 0.047). These haplotypes conferred an increased risk to schizophrenia, restricted to males (P = 0.024, OR = 1.41, 95% CI 1.01-1.90). Thus, pending on replication studies, MAOB seems to fit the ancestral susceptibility model, validating a new strategy to search for common schizophrenia susceptibility genes by focusing in those functional candidate genes subject to recent positive selection.

Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis

“…To our knowledge, two studies have searched for association between this SNP and schizophrenia (http://www.szgene.org) and our results are in accordance with one of these two studies [56], reporting significant association between rs5905512 and schizophrenia only in men, whereas the other study did not find any associations in either gender [57]. Moreover, rs5905512, located in intron 1, is a perfect proxy of a haplotype spanning from intron 1 to intron 3 and being subject to recent selection, in agreement with the ancestral susceptibility hypothesis of schizophrenia [56]. MAOB rs1799836 was also associated with MHPG concentrations in men with psychosis (uncorrected p = 0.001) in the present study.…”

Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission

“…A direct implication of MAOB in schizophrenia is supported by several studies (Coron et al, 1996; Bergen et al, 2009; Carrera et al, 2009; Piton et al, 2011; Wei et al, 2011; Sun et al, 2012a) and may be reflective of the greater contribution of this enzyme to the metabolism of DA in humans. In particular (see Table 2), numerous articles have recently reported that different MAOB variants may predispose to schizophrenia in women (Gasso et al, 2008; Wei et al, 2011) or in men (Wei and Hemmings, 1999).…”

“…Indeed, several groups have reported the association of polymorphic variants of MAOB gene with several neuropsychiatric disorders characterized by DAergic dysfunction. In particular, MAOB allelic variations have been associated with bipolar disorder (Lin et al, 2000) and higher schizophrenia susceptibility (Hovatta et al, 1999; Gasso et al, 2008; Carrera et al, 2009; Piton et al, 2011); these results, however, have been not been consistently replicated (Coron et al, 1996; Sobell et al, 1997; Matsumoto et al, 2004; Bergen et al, 2009). …”

FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies

“…During the last few years, research has been focused on human genome-wide scans of adaptative evolving loci to search for specific modern characteristics in this species [1]. Although most of them are related to fitness, it has been reported that some genes under positive selection in the human lineage can also confer vulnerability to some diseases [2-4]. …”

“…Crespi et al [3] found signals of positive selection in 28 of 76 schizophrenia candidate genes that had been previously reported as positive results in association studies. Evidence of recent positive selection in the human lineage has also been found in haplotypes of MAOB and GABRB2 genes, which also confer an increased risk to schizophrenia [2,4]. Furthermore, brain areas that are differentially dysregulated in schizophrenia include the regions most-notably subject to differential evolutionary change along the human lineage [7-9].…”