# Mendelian Variants Associated with Psychosis

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2020 · $340,178

## Abstract

Psychiatry remains the only medical specialty with diagnosis based solely on reported symptoms. For progress
in personalized medicine, diagnosis must be reliable, sensitive, and specific. Consensus exists the current
diagnostic system (DSM), although useful for clinical description, lacks these requirements. Genetics offers
potential in psychiatric nosology and in the development of novel prevention strategies and treatments.
Numerous variants associated with psychiatric disorders have been discovered recently. These variants if
common have low effects sizes and lack disease specificity; if rare, they typically involve genes with broad
functions and neuropsychiatric phenotypes (e.g., intellectual disability). Historically in medicine, Mendelian
variants have been the first step in understanding the genetic bases of diseases. No single Mendelian variant
has been discovered for any psychiatric disease. Across the world (e.g., Saudi Human Genome Program), the
most successful approach for mutation discovery used whole exome or whole genome sequencing (WES,
WGS) along with homozygosity mapping of consanguineous multiplex pedigrees. US population isolates do
not have the requisite coefficient of inbreeding to apply these methods successfully. However, there is a high
prevalence of marriages between first cousins in several countries: the highest occurs in Pakistan (>60%). This
proposal exploits a newly developed international collaboration (PK, USA): molecular biologists with a track
record of successful gene discovery in consanguineous pedigrees; neuropsychiatrists; clinical neuroscientists;
bioinformaticians; and neuroimagers. The goals are twofold: 1) To find and characterize Mendelian genes
associated with a mental illness; 2) To increase awareness and treatment of mental disorders and to grow
Pakistan’s existing research infrastructure including a Pakistani Human Genome Program focusing on the
study of mental disorders. Were no Mendelian genes found where they are most expected, this result would
provide practical evidence of absence, highly significant in and of itself. If found and because single pedigrees
are likely to have only one rare variant, the mutation would essentially define a homogeneous disorder that can
be studied with methods such as neuroimaging, molecular/cellular biology, and cognitive neuroscience. Aim
one involves the recruitment and characterization of multigenerational, multiplex, consanguineous families
afflicted with psychosis. WES will be followed by informatic analyses including only variants that are rare;
nonsynonymous; protein altering or likely pathogenic; and showing Mendelian in-heritance (homozygous in
affected; heterozygous in obligate carriers). Aim 2 involves increasing within Pakistan the participation of
women in STEM; training the next generation of geneticists; educating about mental diseases; collaborating
and impacting clinical psychiatry; and decreasing stigma. These goals will deliver significance for p...

## Key facts

- **NIH application ID:** 10053078
- **Project number:** 1R21MH120692-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Sadaf Naz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,178
- **Award type:** 1
- **Project period:** 2020-07-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053078

## Citation

> US National Institutes of Health, RePORTER application 10053078, Mendelian Variants Associated with Psychosis (1R21MH120692-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10053078. Licensed CC0.

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