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Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia.

ABSTRACT: The persistence of schizophrenia in human populations at a high prevalence and with a large heritability estimate despite reduced fertility and increased mortality rate is a Darwinian paradox. This may be likely if the genomic components that predispose to schizophrenia are also advantageous for the acquisition of important human traits, such as language and cognition. Accordingly, an emerging group of genomic markers of recent evolution in humans, namely human accelerated regions (HARs), since our divergence from chimpanzees, are gaining importance for neurodevelopmental disorders, such as schizophrenia. We hypothesize that variants within HARs may affect the expression of genes under their control, thus contributing to disease etiology. A total of 49 HAR single nucleotide polymorphisms (SNPs) were prioritized from the complete repertoire of HARs (n = 2737) based on their functional relevance and prevalence in the South Asian population. Test of association using 2 independent schizophrenia case-control cohorts of north Indian ethnicity (discovery: n = 930; replication: n = 1104) revealed 3 SNPs (rs3800926, rs3801844, and rs764453) from chromosome 7 and rs77047799 from chromosome 3 to be significantly associated (combined analysis: Bonferroni corrected P < .002-.000004). Of note, these SNPs were found to alter the expression of neurodevelopmental genes such as SLC25A13, MAD1L1, and ULK4; a few from the HOX gene family; and a few genes that are implicated in mitochondrial function. These SNPs may most likely alter binding sites of transcription factors, including TFCP2, MAFK, SREBF2, E2F1, and/or methylation signatures around these genes. These findings reiterate a neurodevelopmental basis of schizophrenia and also open up a promising avenue to investigate HAR-mediated mitochondrial dysfunction in schizophrenia etiology.

SUBMITTER: Bhattacharyya U

PROVIDER: S-EPMC8759809 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The discovery of the TROSY effect (Pervushin et al. in Proc Natl Acad Sci USA 94:12366-12371, 1997) for reducing transverse relaxation and line sharpening through selecting pathways in which dipole-dipole and CSA Hamiltonians partially cancel each other had a tremendous impact on solution NMR studies of macromolecules. Together with the methyl TROSY (Tugarinov and Kay in J Biomol NMR 28:165-172, 2004) it enabled structural and functional studies of significantly larger systems. The optimal field strengths for TROSY have been estimated to be on spectrometers operating around 900 MHz (21.14 T) for the 1HN TROSY (Pervushin et al. in Proc Natl Acad Sci USA 94:12366-12371, 1997) while the aromatic 13C (13Caro) TROSY is posited to be optimal at around 600 MHz (14.09 T) (Pervushin et al. in J Am Chem Soc 120:6394-6400, 1998b; Pervushin in Q Rev Biophys 33:161-197, 2000). The initial rational was based on the consideration of where the quadratic B0 field dependences of the TROSY relaxation rates reach a minimum. For sensitivity consideration, however, it is interesting to estimate which field strengths yield the tallest peaks. Recent studies of 15N-detected TROSYs suggested that maximal peak heights are expected at 1.15 GHz (27.01 T) although the slowest relaxation rates or longest transverse relaxation times T2 are indeed expected around 900 MHz (21.14 T) (Takeuchi in J Biomol NMR 63:323-331, 2015; Takeuchi et al. in J Biomol NMR 64:143-151, 2016). This was based on the fact that the heights of Lorentzian lines are proportional to B o3/2 * T2 (Bo). Thus, multiplying the parabolic T2(Bo) dependence with the increasing function of B o3/2 shifts the maxima of peak-height field dependence from the T2 maximum at 900 MHz to higher fields. Moreover, besides shifting the peak height maximum for 15N TROSY, this analysis yields estimates for optimal peak heights for 1HN detected TROSY to 1.5 GHz, and to 900 MHz for 13C-detected 13CaroTROSY as is detailed below. To our knowledge, this aspect of field dependence of TROSY sensitivity has not been in the attention of the NMR community but may affect perspectives of NMR at ultra-high fields.

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Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia.

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