biol 1040 - genomics of complex traits

what is a SNP?

a single nucleotide polymorphism - a variation at one nucleotide position in DNA among individuals

what is a phenotype?

an observable characteristic or trait, such as height, eye color, or disease status

what is a genome-wide association study (GWAS)?

a study that examines genetic variation across the genome to identify SNPs statistically associated with a phenotype

what is the primary purpose of a GWAS?

to identify genomic regions associated with a trait or disease, providing clues about where relevant genes may be located

what is a GWAS hit?

a SNP that shows a statistically significant association with the phenotype being studied

does a GWAS hit necessarily identify the casual gene?

no, a GWAS hit identifies an associated genetic marker or region, not necessarily the casual variant or gene

what is linkage disequibilibrium?

a statistical correlation between alleles at different genetic loci

why do genetic variants often show linkage disequilibrium?

nearby variants tend to be inherited together because they are physically close on the chromosome

how can linkage disequilibrium help explain a GWAS association?

a SNP may be associated with a phenotype because it is correlated with a nearby causal variant, even if the SNP itself does not cause the trait

what is the difference between an associated SNP and a casual variant?

an associated SNP statistically correlated with a phenotype; a casual variant directly contributes to variation in that phenotype

what is the basic process of GWAS?

1. collect genetic and phenotype data from a population

2. examine SNPs across the genome

3. identify statistically significant associations

4. investigate associated genomic regions an candidate genes

what is heritability?

a measure of how much variation in a trait within a particular population is statistically associated with genetic differences

what is missing heritability?

the difference between heritability estimates from traditional studies, such as twin studies, and the amount of variation explained by identified genetic variants in GWAS

why might GWAS explain less heritability than twin studies?

GWAS may miss rare variants and variants with very small effects

why might twin studies overestimate heritability?

identical twins share environments, and other complexities may cause traditional twin-study estimates to overstate genetic effects

what are the two explanations for missing heritability?

1. GWAS misses genetic contributions

2. twin studies may overestimate genetic effects

what is a complex trait?

a trait influenced by multiple genetic variants and potentially environmental factors

what is genetic architecture?

the number, distribution, and effects of genetic variants contributing to a trait

what does it mean when a trait has a highly polygenic architecture?

many genetic variants contribute to variation in the trait, often with small individual effects

what is the difference common and rare variants?

common variants generally have small individual effects, whereas rare variants can have larger effects on individuals

what does the lecture suggest about selection and variants with large effects?

the pattern of common variants having smaller effects and rare variants having larger effects is consistent with selection against casual variants with the larger effects

why does the lecture use schizophrenia as an example?

it demonstrates how a complex disease can involve many genetic loci rather than one single disease gene

what did the schizophrenia GWAS described in the lecture examine?

approximately 37,000 cases and 113,000 controls

what did that schizophrenia GWAS identify?

108 associated loci, 83 of them which were new discoveries at the time

what happened as schizophrenia GWAS studies became larger?

researchers identified more associated loci, with a later study identifying 287

what does the large number of schizophrenia-associated loci suggest?

schizophrenia has a complex genetic architecture involving genomic regions

why isn’t there necessarily one "‘schizophrenia gene’?

many genetic variants contribute to susceptibility, often with small effects, rather than one gene determining the outcome

what is the purpose of follow-up sequencing after GWAS?

to investigate associated regions more closely and identify specific variants or candidate genes that may contribute to the phenotype

how do rare variant studies complement GWAS?

GWAS points researchers toward important regions, while rare variant sequencing can help identify specific genes and potentially casual variants

what did the lecture’s GRIN2a example demonstrate?

GWAS signals and rare protein truncating variants overlapped in a genomic region, helping connect association signals to candidate genes

what biological processes were implicated by candidate genes in the schizophrenia example?

several candidate genes were involved in regulating synapses in the brain

why are these genetic discoveries useful?

they reveal biological pathways involved in disease and can open new avenues for drug discovery and treatment research

what is genetic determinism?

the idea that genetic makeup determines traits or outcomes

why is genetic determinism especially sensitive when studying social traits?

because genetic findings may be interpreted as explanations of identity, behavior, or social outcomes, even when the evidence only shows statistical associations

can GWAS study personality or social behaviors?

yes, any measurable phenotype, including survey responses and behavioral characteristics, can potentially be examined for genetic associations

what biological processes were mentioned in that study?

processes involving olfactory senses and sex hormones

why might the number of GWAS hits change when sample size changes?

larger samples can detect smaller associations that may not reach statistical significance in smaller studies

why should GWAS findings about behavior be communicated carefully?

because statistical associations can be oversimplified into claims that a single gene determines a complex behavior or identify

what is the danger of applying population-level genetic findings to individuals

generalizations about a population do not necessarily accurately describe any particular individual

what did the education attainment GWAS described examine?

approximately 1.1 million individuals

what did that education attainment study identify?

1,271 independent genome-wide-signficant SNPs

why is educational attainment a complicated phenotype?

it is influenced by genetic variation as well as social and environmental conditions, including educational opportunities and resources

what is genetic essentialism?

treating genetic differences as fixed or fundamental explanations for traits or differences between people or groups

does heritability mean a trait cannot change?

no - heritability describes variation within a population it does not establish whether a trait is modifiable

how does the lecture use historical IQ trends to challenge genetic essentilaism?

average IQ scores increased overtime alongside changes such as increased educational attainment, demonstrating that environmental conditions can influence outcomes

what does genotype x environment interaction (G x E) mean?

genetic variation can have different effects on a phenotype depending on the environment in which it is expressed

how can environmental influence the relationship between genetics and educational attainment?

different social and educational environments can change how genetic differences relate to educational outcomes

why can systematic inequality complicate genetic studies of educational attainment?

social conditions may differ systematically between populations, meaning genetic associations with educational outcomes can reflect complex relationships between genetic variation and environment

what is central point about social interventions?

genetic contributions to a trait do not mean environmental changes or social interventions are pointless

why should researchers be cautious when interpreting genetic differences between socially defined groups?

social categories are not straightforward proxies for genetic ancestry, and social and historical conditions can influence measured outcomes