Today marks the 25th anniversary of Neil Risch and Kathleen Merikangas' classic 2-page paper that articulated GWAS as the future of human genetics. A short thread.…
Risch and Merikangas argued that linkage mapping had been ineffective at finding complex trait loci, and that association mapping would be far more powerful. In this power analysis they compared allele-sharing (linkage) and TDT (association) tests using trios and quartets:
They showed that the association tests are uniformly more powerful. Roughly speaking this is because it's easier to measure mean shifts than correlations: for small effect size gamma-1=beta the association signal is proportional to beta, while for linkage it's beta^2.
Based on this logic, they argued that association mapping was the only way to achieve successful mapping of complex trait loci -- and that this must be performed genome-wide.
Of course the problem in 1996 was that there was no genome sequence, no genome-wide panel of SNPs, and no technology that could plausibly genotype a million variants. So this vision was like science fiction at that time.
Incidentally, as far as I know, this is also the first paper to suggest the conventional genome-wide significance threshold of 5e-8.
It's hard to overstate the impact of this 2-page thought-experiment in driving the direction of human genetics over the next decade and beyond.
It was truly the paper that launched a thousand chips
I also have a debt of gratitude to Neil, as I became interested in human genetics through a couple of classes that he taught at Stanford in 97-98 when I was a student. He was a talented teacher, and I believe 5 current Stanford faculty were in that 1998 statgen class.

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More from @jkpritch

7 Aug
What an amazing Olympics that was, despite everything! Here are some (track) highlights from my perspective, with video clips. My performers of the meet: Sifan Hassan and Karsten Warholm.
In case you missed it, the Dutch woman Sifan Hassan won two golds (5+10) and bronze (1500). It's hard to put into words how awesome her range is +her huge kick. Here she falls in a qualifying round of the 1500, gets up to win (and wins the 5000 that night)
The M 400 hurdles with Karsten Warholm (Norway) and Rai Benjamin (US) was always going to be epic. Warholm had recently broken the 29 year world record, and Benjamin was nearly as fast at the US trials. Their race in Tokyo was one for the history books
Read 17 tweets
23 Apr 20
Yesterday I ran a thread about our new paper using UK Biobank GWAS to identify core genes for several traits:

Today I want to expand on some fascinating things that we learned about sex differences in testosterone.
We and other groups have recently noticed strong sex differences between males and females in testosterone genetics (our analysis led by Sahin Naqvi @snaqvi1990 and Nasa Sinnott-Armstrong). Lead hits for testosterone share ~no overlap, and highlight different types of genes Image
Another way to look at this is by comparing effect sizes for hit SNPs in females vs males. No correlation. The insets show two other traits that are more typical (urate, SHBG). The genomewide genetic correlation by LDSR is also ~0. Image
Read 15 tweets
22 Apr 20
Our latest: "GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background":…
We use urate, IGF-1, and testosterone as model molecular traits to learn general principles about the architecture of complex traits.
Most importantly, this project is thanks to wonderful work by Nasa Sinnott-Armstrong and Sahin Naqvi @snaqvi1990 in my lab; thanks also @manuelrivascruz whose work with Nasa doing GWAS of UK Biobank biomarkers led to this project.
We picked urate, IGF-1 and testosterone as models for complex trait architecture.

All 3 traits show strong enrichment of genes involved in the relevant synthesis, transport or signaling pathways, depending on the trait. However, most h^2 comes from a huge polygenic background.
Read 18 tweets
7 Nov 19
Delighted to share our latest work, on ancient DNA of individuals from in and around Rome, spanning the last 12,000 years. At its peak Rome was the largest city of the ancient world with 1M inhabitants, controlling an empire of 70M people…
This was a wonderful collaboration with Ron Pinhasi and Alfredo Coppa; work was led by amazing people in my lab: @antmarge, @ziyue_gao, @mootspoints and other fantastic collaborators: @gaspi60 @ersilia_maria @diegoisworking @daniMfernandes @SerenaAneli @danjcotter @bigskybioarch
We sequenced 127 genomes, from 29 archaeological sites in Rome and central Italy. These span from the Mesolithic to the Medieval period. We see two major population transitions, corresponding to influxes of Neolithic and Steppe ancestry, as seen elsewhere in Europe.
Read 12 tweets

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