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IMF-092-02-0001-en	Why can recessive or late-onset disease alleles reach appreciable frequency while severe early-onset dominant variants rarely do?	Negative selection removes alleles with severe dominant effects, but recessive, late-onset, low-penetrance or selected alleles can persist, so rare does not mean pathogenic nor common harmless.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0002-en	How can a founder effect raise a disease allele's frequency, and what caveat applies to founder-variant testing?	A new population may carry an unrepresentative subset of source variation, raising rare alleles without advantage; a founder variant aids targeted testing but must not replace broader analysis in heterogeneous populations.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0003-en	Why does the sickle-haemoglobin allele persist despite causing severe disease in homozygotes?	Balancing selection through heterozygote advantage maintains it, because heterozygotes have reduced malaria severity, though modern environments can change this historical trade-off.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0004-en	Why is socially defined race a poor substitute for genotype?	Human variation is largely shared with gradual frequency differences and no discrete biological races; race captures lived exposures, discrimination and structural factors rather than genotype or causal biology.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0005-en	For a rare recessive allele, when does the estimate that carrier frequency is about twice the allele frequency fail?	It fails with founder structure, assortative mating or multiple variants, because the estimate assumes Hardy–Weinberg conditions; carrier screening should use measured population data.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0006-en	Why should the lead marker of an association signal not be assumed to be the causal variant?	A genotyped marker can tag an unmeasured causal variant through linkage disequilibrium, which differs among ancestry groups, so fine mapping seeks the causal set.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0007-en	Why does high heritability not mean a trait is unchangeable by environment?	Heritability is a share of phenotypic variance in a particular population and environment, not the genetic share of an individual's trait; phenylketonuria under dietary treatment shows both can coexist.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0008-en	How can gene–environment correlation be mistaken for gene–environment interaction?	When genotypes influence exposure, for example through behaviour shaping environment, the two become linked and can mimic interaction, so causal claims require careful design.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0009-en	How does population stratification produce a spurious genetic association?	When ancestry relates both to allele frequency and to phenotype through genetic or environmental pathways, it confounds the association; principal components and mixed models reduce but may not eliminate this.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0010-en	Why can an odds ratio from a case–control study mislead about risk?	An odds ratio is not absolute risk and may overstate the risk ratio when the outcome is common, while winner's curse inflates effects estimated at discovery.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0011-en	What limits the interpretation of a polygenic score for an individual patient?	It stratifies relative risk within populations and depends on ancestry, calibration, age and context; a high score is not diagnosis, and a low score does not exclude monogenic disease or environmental risk.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0012-en	What must hold for a genetic instrument in Mendelian randomisation, and what can violate it?	The variant must associate with the exposure, be independent of confounders and affect outcome only through exposure; pleiotropy, population structure, developmental compensation and selection can violate this.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0013-en	Why do penetrance estimates from affected families and from population biobanks tend to differ?	Affected-family estimates are often inflated by ascertainment, while biobanks may give lower estimates but underrepresent severe childhood disease and diverse groups.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending
IMF-092-02-0014-en	Why does a variant's absence from a population allele database not establish pathogenicity?	Absence supports only rarity, and databases have uneven ancestry, age, relatedness and disease representation; by contrast, a frequency incompatible with disease argues against a fully penetrant model.	Integrated Medical Foundations; chapter 92, TTS module 2; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 43bd3ef9774b4a587aee9129d280914601aaa31e901a6a91e1db1ce19054a2e5; editorial review pending	imf lang::en chapter::092 module::092-02 review::pending