Road Map to Precision Psychiatry: Comprehensive Investigation of Chromosomal Anomalies (PsychMap) - Summary
Background: While the past decade has provided insight into the genetic architecture of complex traits and
disorders, the identified genetic associations are fraught with complex patterns of heterogeneity and clinical
pleiotropy, especially in psychiatry. Also, little is yet known about pathogenic and societal impact of disease-
predisposing genomic variants at the level of an individual or an entire population, since many of them confer
very modest increases in disease risk. Recurrent copy number variants (CNVs) and sex chromosome
aneuploidies (SCAs) are well suited to break the impasse and pilot efforts in precision psychiatry with their
reasonable prevalence and sizable disease risk.
Aims: We will first provide truly unbiased estimates of prevalence, as well as age-dependent hazard and disease
penetrance, of recurrent CNVs and SCA; second, determine the global burden of disease (GBD) of these
genomic alterations; and third, transform these findings into clinical recommendations for actionable genetic
testing and planning of healthcare provision. Additionally, we will determine the degree to which pathologic
profiles of CNV/SCA differ between clinically ascertained carriers (who form the basis of most hitherto research
of pathogenicity of CNVs/SCAs) and carriers whose carrier status is unknown by the healthcare system.
Methods: We will (a) leverage a genotyped case-cohort psychiatric sample truly representative of the Danish
population (n[psych]=90.000; n[cohort]=50,000) to determine carrier status of recurrent CNVs at 54 genomic loci
as well as for SCA, (b) cross-reference detailed clinical, demographic and socio-economic person-level data
from public, nationwide registries, in order to (c) estimate for each of the chromosomal anomalies (i) the
Population prevalence, Penetrance and Hazards for individual psychiatric and somatic diagnoses, (ii) the
corresponding life-time disease trajectories and (iii) the disease burden, using (d) (i) Cox Proportional Hazards
models with inverse sampling probability weights, (ii) Sequence Analysis and (iii) standard health economic
measures, incl. DALY and direct and indirect healthcare costs. Some of these methods have been developed
specifically over the last years in cooperation between the research groups of the Danish and U.S. based
applicants. To determine the impact of ascertainment bias on perceived disease rates of carriers, we’ll cross-
reference the Danish population sample carriers with records from the Danish cytogenetic register and compare
clinically known vs. unknown carriers, and also compare overall disease rate in the Danish population sample
carriers with a large clinical sample of SCA carriers from the U.S.
