The looming crisis in human genetics

Nov 13th 2009

From The World in 2010 print edition
By Geoffrey Miller

Some awkward news ahead

Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.

About five years ago, genetics researchers became excited about new methods for “genome-wide association studies” (GWAS). We already knew from twin, family and adoption studies that all human traits are heritable: genetic differences explain much of the variation between individuals. We knew the genes were there; we just had to find them. Companies such as Illumina and Affymetrix produced DNA chips that allowed researchers to test up to 1m genetic variants for their statistical association with specific traits. America’s National Institutes of Health and Britain’s Wellcome Trust gave huge research grants for gene-hunting. Thousands of researchers jumped on the GWAS bandwagon. Lab groups formed and international research consortia congealed. The quantity of published GWAS research has soared.

In 2010, GWAS fever will reach its peak. Dozens of papers will report specific genes associated with almost every imaginable trait—intelligence, personality, religiosity, sexuality, longevity, economic risk-taking, consumer preferences, leisure interests and political attitudes. The data are already collected, with DNA samples from large populations already measured for these traits. It’s just a matter of doing the statistics and writing up the papers for Nature Genetics. The gold rush is on throughout the leading behaviour-genetics centres in London, Amsterdam, Boston, Boulder and Brisbane.

GWAS researchers will, in public, continue trumpeting their successes to science journalists and Science magazine. They will reassure Big Pharma and the grant agencies that GWAS will identify the genes that explain most of the variation in heart disease, cancer, obesity, depression, schizophrenia, Alzheimer’s and ageing itself. Those genes will illuminate the biochemical pathways underlying disease, which will yield new genetic tests and blockbuster drugs. Keep holding your breath for a golden age of health, happiness and longevity.

In private, though, the more thoughtful GWAS researchers are troubled. They hold small, discreet conferences on the “missing heritability” problem: if all these human traits are heritable, why are GWAS studies failing so often? The DNA chips should already have identified some important genes behind physical and mental health. They simply have not been delivering the goods.

Certainly GWAS papers have reported a couple of hundred genetic variants that show statistically significant associations with a few traits. But the genes typically do not replicate across studies. Even when they do replicate, they never explain more than a tiny fraction of any interesting trait. In fact, classical Mendelian genetics based on family studies has identified far more disease-risk genes with larger effects than GWAS research has so far.

Why the failure? The missing heritability may reflect limitations of DNA-chip design: GWAS methods so far focus on relatively common genetic variants in regions of DNA that code for proteins. They under-sample rare variants and DNA regions translated into non-coding RNA, which seems to orchestrate most organic development in vertebrates. Or it may be that thousands of small mutations disrupt body and brain in different ways in different populations. At worst, each human trait may depend on hundreds of thousands of genetic variants that add up through gene-expression patterns of mind-numbing complexity.