Polygenic score analysis of Bipolar Disorder Pubblico

Abstract

Bipolar Disorder (BD) is a life-long mental disorder with a high heritability. Although no single gene explains the disease, a great number of studies successfully identified the combined effect of small genetic factors contributing to BD. Polygenic risk score (PRS) is generated by counting and weighing these risk alleles among target individuals. In this study, we examine whether PRS generated from Bipolar I Disorder (BPI) is able to predict BPI status, age at onset of psychosis and Schizophrenia (SZ) status. We first used the entire BPI and controls set to identify associated SNPs at three inclusion thresholds (P<0.1, P<0.05, P< 0.001) and used these variants to calculate PRS in the exact same population. Afterwards, we divided the dataset evenly into a training set in which we obtained the genetic risk variants and a replication set in which we generated the PRSs. Last, we tested the PRS from the BPI in SZ patients. The results showed that the PRSs were significant higher among BPI cases compared to controls, regardless of the threshold in the original dataset (P<0.0001). The PRS from BD risk alleles were also higher among SZ cases compared to controls at threshold P<0.05 (P=0.0003) and threshold P<0.001 (0.0222). Nonetheless, the PRSs did not differ significantly between BPI cases and controls in the replication sample. Likewise, PRSs were unable to predict age at onset of psychosis in both dataset.

Table of Contents

Background .....................................................................................................................................1

Risk Factors for BD ..........................................................................................................................5

Environmental and other factors ......................................................................................................5

Genetic factors ...............................................................................................................................5

Candidate Gene Associations ...........................................................................................................6

Overlap in genetics of Bipolar Disorder and Schizophrenia ................................................................9

Polygenic risk score .......................................................................................................................10

METHODS ....................................................................................................................................12

Study Questions and Hypothesis ....................................................................................................12

Material .......................................................................................................................................12

Study Sample ...............................................................................................................................12

Source of genetic data ..................................................................................................................13

Method .......................................................................................................................................14

Data cleaning ..............................................................................................................................14

GWAS and risk score calculation ...................................................................................................14

Analysis of polygenic risk scores ...................................................................................................15

Analysis of SZ samples .................................................................................................................16

RESULTS .................................................................................................................................... 18

DISCUSSION ...............................................................................................................................23

FUTURE DIRECTIONS ..................................................................................................................26

References ...................................................................................................................................27

TABLES .......................................................................................................................................36

FIGURES AND FIGURE LEGENDS ..................................................................................................37

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MSPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Parola chiave	Polygenic risk score Bipolar Disorder
Committee Chair / Thesis Advisor	Mulle, Jennifer, Emory University

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