Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance Jibin John a,e , Upasana Bhattacharyya a,1 , Navneesh Yadav a,1 , Prachi Kukshal a , Triptish Bhatia b , V.L. Nimgaonkar c,d , Smita N. Deshpande b , B.K. Thelma a, ⁎ a Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India b Department of Psychiatry, PGIMER-Dr. RML Hospital, New Delhi 110 001, India c Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213, USA d Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, DeSoto St, Pittsburgh, PA 15213, USA e Department of Neurology and Neurosurgery and Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, H3A 2B4, Canada abstract article info Article history: Received 9 April 2019 Received in revised form 23 November 2019 Accepted 24 November 2019 Available online xxxx Keywords: Schizophrenia Exome sequencing Epigenetics Neurodevelopment TNIK Oligogenic Schizophrenia is a clinically and genetically heterogeneous neuropsychiatric disorder, with a polygenic basis but identification of the specific determinants is a continuing challenge. In this study, we analyzed a multigenera- tional family, with all healthy individuals in the first two generations, and four progeny affected with schizophre- nia in the subsequent two generations, using whole exome sequencing. We identified five rare protein sequence altering heterozygous variants, in five different genes namely SMARCA5, PDE1B, TNIK, SMARCA2 and FLRT shared among all affected members and predicted to be damaging. Variants in SMARCA5 and PDE1B were inherited from the unaffected father whereas variants in TNIK, SMARCA2 and FLRT1 were inherited from the unaffected mother in all the three affected individuals in the third generation; and notably all these five variants were transmitted by an affected mother to her affected son. Microsatellite based analysis lent a modest linkage support (LOD score of 1.2; θ=0.0 at each variant). Of note, analysis of exome data of an ancestry matched unrelated schizophrenia cohort (n = 350), revealed a total of 16 rare variants (MAF b 0.01) in these five genes. Interestingly, these five genes involved in neurodevelopmental and/or neuro- transmitter signaling processes are implicated in the etiology of schizophrenia previously. This study provides good evidence for a likely cumulative contribution of multiple rare variants from disease relevant genes with a threshold effect in disease development and seems to explain the unusual disease transmission pattern generally witnessed in such conditions, but warrants extensive replication efforts in families with similar complex disease inheritance profiles. © 2019 Elsevier B.V. All rights reserved. 1. Introduction Schizophrenia (SZ) is a severe neuropsychiatric disorder, commonly believed to arise from a complex interplay between genetic and envi- ronmental risk factors that influences early brain development and causes significant disability and early mortality. With onset of illness in early adolescence (Crome, 2017; Hjorthøj et al., 2017; Kahn et al., 2015; Pulver et al., 1990; Walker et al., 2015) it is expressed as a combi- nation of positive symptoms such as hallucinations, delusions and neg- ative symptoms including social withdrawal, affective flattening, anhedonia, diminished initiative and energy (McGlashan and Fenton, 1992). More than 98% of SZ patients also suffer from neurocognitive im- pairment (Heinrichs and Zakzanis, 1998; Zai et al., 2017). Deficits in synaptic formation and function due to early neurodevelopmental ab- normalities are also reported (Corroon, 2005; Stachowiak et al., 2013). Knowledge underlying disease etiology is still limited, but altered dopamine, glutamate, serotonin and Gamma Amino Butyric Acid (GABA) activity have been reported in SZ (Frohlich and Van Horn, 2014; Harrison and Weinberger, 2005; Schiffer, 2002; Stone, 2011; Stone et al., 2008; Thornberg and Saklad, 1996; Wang et al., 2011). On the other hand, a large number of family, twin and adoption studies in the pre-molecular genetics era, using a range of ascertainment and as- sessment rules, have consistently shown the importance of genetic fac- tors in SZ (Gejman et al., 2011). However, in spite of high heritability (Cannon et al., 1998; Lichtenstein et al., 2009), and notable advances in technology from early linkage analysis, through candidate gene and genome-wide association studies (GWASs) to whole exome/genome sequencing, identification of genetic risk remains a challenge. GWAS performed by the Schizophrenia Working Group of the Psychiatric Ge- nomics Consortium, has identified 108 risk loci with genome-wide Schizophrenia Research xxx (xxxx) xxx ⁎ Corresponding author. E-mail address: thelmabk@gmail.com (B.K. Thelma). 1 Equal contributions. SCHRES-08588; No of Pages 7 https://doi.org/10.1016/j.schres.2019.11.041 0920-9964/© 2019 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: J. John, U. Bhattacharyya, N. Yadav, et al., Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex m..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.11.041