Sunday, December 22, 2024
12/22/2024
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.
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