Transcript who, icidh, 1980

Comorbidity:
The aetiological / genetic
perspective
Martina C. Cornel, professor of
community genetics & public health
genomics
Research Programme >
Quality of Care
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 (1990-2000)
• 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