Quality of CareResearch Programme > Comorbidity: The aetiological / genetic perspective Martina C. Cornel, professor of community genetics & public health genomics Clinical Genetics/ EMGO Institute for Health & Care Research

Definition “condition” Comorbidity: co-existent “conditions” Etiology → pathology → manifestation Disease → impairment → disability → handicap WHO, ICIDH, 1980 Question of patient relates to consequences of disease: –Feel sad, apathy, headache, cannot go to work, do not manage to perform daily activities, diminished participation, lack of social integration

Definition “condition” Comorbidity: co-existent “conditions”: Etiology → pathology → manifestation Disease → impairment → disability → handicap WHO, ICIDH, 1980 Etiology or pathology or disease or impairment? Epilepsy, dementia, depression?

Etiological diagnosis in genetics Down syndrome due to translocation of chromosomes #21 & 14, inherited from mother Epicanthus, simian crease, congenital cardiac anomaly

Patterns of malformations in genetics Syndromes: Consistent and recognizable patterns of abnormalities for which there will often be a known underlying cause (Down; one cause, several effects) Sequences: Consequence of a cascade of events initiated by a single primary factor (Potter: renal agenesis → oligohydramnios → pulmonary hypoplasia and fetal compression → dislocation of hips and talipes). Associations: non-random occurrence of abnormalities that cannot be explained on the basis of a sequence or syndrome. Emery, 2007

Comorbidity: Causes? Consequences? Syndromes: One cause, several consequences Sequences: Cause, consequence, consequence of consequence Associations: recognized pattern in the absence of satisfactory underlying explanation

Recent developments in genetics/genomics One gene, one disease ( ) Human genome sequenced (2001) Genomics research (2001 → ) –Function of genes –DNA, RNA, proteins, metabolites –High throughput –Common disorders –Multifactorial disorders

One gene, one disease Heutink 1994

One gene, one disease Heutink 1994

Common disease, common variant? Heutink 1994

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls The Welcome Trust Case Control Consortium, Nature 2007

Contributing factors in causal models Janssens 2008

One disease, several genes; One gene, several diseases Frazer et al. Nat Rev Genet 2009

Common diseases, common pathways Zhernakova et al 2009

Comorbidity and genetics Monocausal One genotype, several consequences (del 22q11 → cleft palate & schizophrenia & bipolar disorder) Multifactorial Gene variant associated with increased risk of several multifactorial disorders Gene function gives information about pathway (pathogenesis) Treatment/prevention based on pathway

Comorbidity and genetics The challenge in 2009 for common complex disorders: –Homogeneous subgroups (define phenotype) –Identify genes involved in multifactorial disorders –Identify common pathways –Develop treatment (or prevention) tailored to pathway → both co-existent disorders

Take home message Comorbidity may reflect common etiological pathway –One gene/one cause or –Multiple susceptibility genes Genetics/genomics can help to identify common pathways