A groundbreaking discovery reveals that what we thought about genetic inheritance might only be the tip of the iceberg.
Imagine your genetic code as a lengthy book, and most researchers have been focusing on the common typographical errors that appear in many copies. But what if the most consequential mistakes were the rare, unique typos that appear in only a handful of copies? This is the story of how scientists investigating a crucial lung-protecting protein discovered that rare genetic variants, previously too difficult to study, hold the key to understanding a widespread deficiency that affects millions worldwide. The journey to this discovery would challenge established thinking about genetics and reveal a hidden layer of our biological inheritance that had been in plain sight all along.
Common genetic variants were once thought to be the primary drivers of disease risk, but new research reveals that rare variants play a much larger role than previously recognized in conditions like alpha-1 antitrypsin deficiency.
To understand this genetic breakthrough, we must first meet the protagonist of our story: alpha-1 antitrypsin (AAT). This remarkable protein, produced primarily in our livers, serves as a crucial defender of our lung tissue. Think of AAT as a dedicated security guard that neutralizes neutrophil elastase—a powerful enzyme that, when unchecked, can damage the delicate air sacs in our lungs like an unsupervised demolition crew 8 9 .
Alpha-1 antitrypsin protects lung tissue by inhibiting neutrophil elastase, maintaining the structural integrity of alveoli.
Without sufficient AAT, neutrophil elastase damages lung tissue, leading to emphysema and COPD.
When this protective system fails due to alpha-1 antitrypsin deficiency (AATD), the consequences can be severe. The uninhibited enzyme breakdown leads to the destruction of lung tissue, resulting in emphysema and chronic obstructive pulmonary disease (COPD), often at an unexpectedly early age. In some cases, the misfolded AAT protein also accumulates in the liver, potentially causing liver damage and cirrhosis 9 .
The instruction manual for producing this vital protein is encoded in the SERPINA1 gene, located on chromosome 14. When this gene contains errors, the production or function of AAT is compromised. For decades, scientists have known about several uncommon variants of this gene, particularly the S and Z variants, which substantially reduce AAT levels in the blood 1 3 .
For years, the conventional wisdom suggested that the S and Z variants were the primary genetic culprits behind AAT deficiency. Yet a puzzling question remained: could more common genetic variations also play a significant role in determining AAT levels and consequently influence lung health?
In many hereditary conditions, including AATD, the known genetic variants cannot fully explain why the disease manifests differently across individuals or families. Scientists suspected that part of the answer might lie in more common genetic variations that had been overlooked 3 4 .
The challenge was technical as much as conceptual. While the rare S and Z variants were well-studied, investigating the potential role of common single nucleotide polymorphisms (SNPs)—which affect more than 5% of the population—required examining the entire genetic landscape without preconceived notions of where to look. This called for a comprehensive approach known as a genome-wide association study (GWAS), which scans the entire genome for clues 3 .
In 2013, an international team of researchers led by Gian Andri Thun embarked on an ambitious quest to solve this genetic mystery. Their study, provocatively titled "Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels," would employ multiple sophisticated genetic techniques to unravel the complex relationship between our DNA and AAT levels 1 3 .
The research design was both meticulous and comprehensive, analyzing data from thousands of participants across two distinct population groups—the Swiss SAPALDIA cohort and the Danish Copenhagen City Heart Study. This multi-tiered approach allowed the scientists to make discoveries in one group and then verify them in another, ensuring their findings weren't limited to a specific population 3 4 .
What made this study particularly innovative was its sequential methodology:
This approach resembled first using a wide-angle lens to survey the entire genetic landscape, then switching to a powerful microscope to examine the most promising areas in exquisite detail 3 .
The first phase of the study yielded exciting results. When researchers scanned the genomes of 1,392 individuals from the SAPALDIA cohort, they identified five common genetic variants that reached genome-wide significance—meaning the statistical association was too strong to be due to random chance. All these significant variants were located in the same neighborhood of our genetic code: the SERPINA gene cluster on chromosome 14 3 .
The most strongly associated variant, dubbed rs4905179, was estimated to reduce AAT levels by 0.068 grams per liter for each copy of the minor allele a person carried. The probability that this association occurred by chance was astronomically low—approximately 1 in 10 trillion (P = 1.20×10^(-12)) 3 .
| SNP | Chromosome Position | Gene Location | Minor Allele Frequency | Effect on AAT (g/L) | P-value |
|---|---|---|---|---|---|
| rs2736887 | 93882733 | Intergenic | 18.5% | -0.071 | 2.48×10^(-13) |
| rs4905179 | 93865245 | SERPINA6 | 18.0% | -0.068 | 1.20×10^(-12) |
| rs7151526 | 93933389 | SERPINA1 | 6.5% | -0.116 | 6.78×10^(-13) |
At this point, the story might seem straightforward—scientists had identified common genetic variants linked to AAT levels. But the researchers recognized that correlation doesn't necessarily imply causation. The observed associations might be what geneticists call "synthetic associations"—signals that appear strong but are actually generated by rare, causal variants lurking in the background 3 4 .
To test this possibility, the team performed a stepwise conditional analysis. This sophisticated statistical approach allows researchers to determine whether a genetic variant independently influences a trait, or whether its apparent effect disappears when they account for other nearby variants 3 .
Effect size of rs4905179
P < 0.0001
Effect size of rs4905179
P = 0.57
Table 2: Replication of Findings in the Copenhagen City Heart Study 3 4
The results were striking. When the researchers statistically controlled for the effects of the well-known PI S and PI Z variants, the strong association between the common SNPs (including the top hit rs4905179) and AAT serum levels vanished completely. The effect was no longer statistically significant (P = 0.57), indicating that these common variants were merely "synthetic associations" reflecting the presence of the rarer, functional S and Z variants 3 4 .
What does it take to conduct such sophisticated genetic research? Here are some of the essential tools and methods that enabled these discoveries:
| Research Tool | Function in the Study | Key Insight |
|---|---|---|
| Genome-wide SNP arrays | Genotyping of common variants across the entire genome | Enabled agnostic discovery of associated regions without prior hypotheses |
| Immunoassays | Precise measurement of AAT serum concentrations | Provided quantitative trait data for association analyses |
| Isoelectric focusing (IEF) | Protein phenotyping to identify S and Z variants | Allowed researchers to account for known functional variants |
| Stepwise conditional analysis | Statistical method to test independence of genetic associations | Revealed that common variants were not causal |
| Exome sequencing | Identification of rare variants in coding regions | Provided comprehensive variant catalog for the gene cluster |
Having established that rare variants, not common ones, primarily determine AAT serum levels, the researchers extended their investigation to explore the implications for lung health. Would they find the same pattern when examining lung function measurements?
This nuanced finding highlights an important principle in genetics: the same variant may have different effects depending on an individual's overall health status and environmental exposures. For those with already compromised lungs, the protective effect of AAT becomes more critical, making deficiency-causing variants more impactful.
This research provided what the authors termed a "textbook example" of how a large portion of a trait's heritability can be concealed in infrequent genetic polymorphisms 4 . The study demonstrated that even strong signals from common variants in genome-wide studies might sometimes be proxies for the cumulative effects of multiple rare variants.
This insight has implications far beyond AAT deficiency, potentially influencing how scientists interpret GWAS results for many complex diseases. It suggests that to fully understand the genetic architecture of many conditions, we must look beyond common variants and develop better methods for detecting the contribution of rare variants.
The findings also carry practical significance for diagnosing and managing AAT deficiency. They underscore the importance of direct testing for S and Z variants rather than relying on indirect genetic markers. They also help explain why AAT deficiency has been so underdiagnosed—with estimates suggesting up to 85% of cases go unrecognized 5 .
Recent advances in genetic testing technology, including the development of tests that can simultaneously analyze multiple AATD mutations using DNA from a simple buccal swab or dried blood spot, promise to improve detection rates 5 . As genetic testing becomes more accessible, it may become feasible to screen broader populations, particularly those with COPD or other risk factors.
The journey to understand how variants in the SERPINA gene cluster influence alpha-1 antitrypsin serum levels illustrates both the power and limitations of modern genetic approaches. It demonstrates that even when sophisticated genome-wide scans identify strong signals, we must dig deeper to distinguish correlation from causation.
This research reminds us that the genetic landscape is more complex than it might initially appear. What seems like obvious culprits—common genetic variants with strong statistical associations—may sometimes be mere bystanders, while the real players are rare variants that have escaped notice.
For the millions living with AAT deficiency and other genetic conditions, these findings represent hope—that through continued rigorous science, we can unravel the complexities of our DNA and translate these insights into better diagnosis, treatment, and ultimately, prevention of genetic diseases.
As the authors aptly noted, this locus represents how "a large part of a trait's heritability can be hidden in infrequent genetic polymorphisms" 4 . As genetic technologies continue to advance, allowing for more comprehensive sequencing of rare variants at lower cost, we can anticipate more discoveries of this nature across many diseases. The story of AAT deficiency serves as both a case study and a cautionary tale—reminding us that in the complex tapestry of our genetic code, important answers often lie in the details we have yet to examine closely.