| Summary: | <p><strong>Background</strong> Although it is known that variation in the <i>aldehyde dehydrogenase 2</i> (<i>ALDH2</i>) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited.</p>
<p><strong>Methods</strong> We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake.</p>
<p><strong>Results</strong> We identified variants in the region of <i>ALDH2</i> strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (<i>ADH1B</i>) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (<i>ALDH2</i>-rs671 and <i>ADH1B</i>-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke).</p>
<p><strong>Conclusion</strong> This study confirms that <i>ALDH2</i>-rs671 and <i>ADH1B</i>-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.</p>
<p><strong>Trial registration</strong> This study only used secondary data.</p>
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