Universität zu Köln

Fatima, Ambrin, Abdullah, Uzma ORCID: 0000-0002-7168-8266, Farooq, Muhammad, Mang, Yuan, Mehrjouy, Mana M., Asif, Maria, Ali, Zafar ORCID: 0000-0002-2389-3337, Tommerup, Niels and Baig, Shahid M. (2021). Rare Pathogenic Variants in Genes Implicated in Glutamatergic Neurotransmission Pathway Segregate with Schizophrenia in Pakistani Families. Genes, 12 (12). BASEL: MDPI. ISSN 2073-4425

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Abstract

Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fatima, Ambrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdullah, Uzma UNSPECIFIED orcid.org/0000-0002-7168-8266 UNSPECIFIED Farooq, Muhammad UNSPECIFIED UNSPECIFIED UNSPECIFIED Mang, Yuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mehrjouy, Mana M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Asif, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Ali, Zafar UNSPECIFIED orcid.org/0000-0002-2389-3337 UNSPECIFIED Tommerup, Niels UNSPECIFIED UNSPECIFIED UNSPECIFIED Baig, Shahid M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-595444
DOI:	10.3390/genes12121899
Journal or Publication Title:	Genes
Volume:	12
Number:	12
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2073-4425
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; RECEPTOR 5; CMYA5; RISK; EXPRESSION; MUTATIONS; MYOSPRYN; SUSCEPTIBILITY; HERITABILITY; INDIVIDUALS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59544