My first interactions with Professor Nicholas (Nick) G. Martin occurred at the end of my PhD during the inaugural Australasian Human Gene Mapping (‘GeneMappers’) Meeting held in Thredbo (NSW, Australia) in early February 1999 — a couple of weeks before I flew to New York to begin my first postdoc in Jurg Ott’s Statistical Genetics Laboratory at Rockefeller University.
I vividly recall (okay, foggily recall [there may have been alcohol involved]) lively discussions on gene mapping and encouragement to contact him should I want to continue my research career upon returning to Australia. Less than two years later and I was sitting in Nick’s office with a lovely view of the Brisbane skyline finalizing my NHMRC early career (Peter Doherty) fellowship application. From these early interactions, I learnt that Nick always spoke his mind (often with wild abandon), but he was always motivated by a desire to perform good science. It is this infectious passion for science that attracts and inspires those around him.
My fellowship application was successful, and a few months later, I began my journey as Nick’s colleague and collaborator within his Genetic Epidemiology Laboratory.
Nick created and continues to maintain a world-class research environment that is rich in data, expertise and excellence. I will always be grateful for the opportunity to learn and benefit from this environment. Indeed, although I was initially attracted to Nick’s lab to ask new and deep questions that extended my PhD research on migraine genetics, I was able to both lead and contribute to hundreds of genetic studies comprising dozens of traits — prominent examples include depression (Yang et al., Reference Yang, Zhao, Boomsma, Ligthart, Belin, Smith and Nyholt2018), endometriosis (Nyholt et al., Reference Nyholt, Gillespie, Merikangas, Treloar, Martin and Montgomery2009; Sapkota et al., Reference Sapkota, Steinthorsdottir, Morris, Fassbender, Rahmioglu, De Vivo and Nyholt2017), leukocyte telomere length (Broer et al., Reference Broer, Codd, Nyholt, Deelen, Mangino, Willemsen and Boomsma2013), male pattern baldness (Nyholt et al., Reference Nyholt, Gillespie, Heath and Martin2003), obesity (Locke et al., Reference Locke, Kahali, Berndt, Justice, Pers, Day and Speliotes2015; Rahmioglu et al., Reference Rahmioglu, Macgregor, Drong, Hedman, Harris, Randall and Zondervan2015) and twinning (Mbarek et al., Reference Mbarek, Steinberg, Nyholt, Gordon, Miller, McRae and Boomsma2016).
Our collaborative research has produced important advances and paradigm changes. For example, one of our first publications rebuked the widely accepted opinion that common baldness was an autosomal dominant phenotype in men and an autosomal recessive phenotype in women. In this first large-scale study of 476 monozygotic (MZ) and 408 dizygotic (DZ) male twin pairs, we estimated a heritability of 0.81 (95% CI [0.77, 0.85]) and indicated that additive genetic effects play a major part in the progression of common male hair loss (Nyholt et al., Reference Nyholt, Gillespie, Heath and Martin2003).
Similarly, our migraine research applied latent class and twin genetic analyses to identify subgroups of migraine sufferers and show the existence of a severity continuum, where migraine with aura (MA) is more severe, but not, as previously thought, etiologically distinct from migraine without aura (Nyholt et al., Reference Nyholt, Gillespie, Heath, Merikangas, Duffy and Martin2004). This research attracted international attention and led to high impact migraine collaborations that persist today. Indeed, this research, together with Nick’s extensive network of international twin/genetic researchers, led to the cofounding of the International Headache Genetics Consortium (IHGC), which brought together headache geneticists and clinicians from around the globe to conduct numerous large-scale genetic studies on migraine (Anttila et al., Reference Anttila, Kallela, Oswell, Kaunisto, Nyholt, Hamalainen and Palotie2006, Reference Anttila, Nyholt, Kallela, Artto, Vepsalainen, Jakkula and Palotie2008; Ligthart et al., Reference Ligthart, Boomsma, Martin, Stubbe and Nyholt2006, Reference Ligthart, Nyholt, Hottenga, Distel, Willemsen and Boomsma2008; Mulder et al., Reference Mulder, Van Baal, Gaist, Kallela, Kaprio, Svensson and Palotie2003; Nyholt et al., Reference Nyholt, Morley, Ferreira, Medland, Boomsma, Heath and Martin2005; van den Maagdenberg et al., Reference van den Maagdenberg, Nyholt and Anttila2019).
With advancing genotyping technology, our migraine research was at the forefront of genetic association studies. Our 2008 IHGC publication showed that contrary to the leading hypothesis at the time, ion transport genes — implicated in familial hemiplegic migraine (FHM), a Mendelian subtype of MA associated with hemiparesis — did not play a major role in the common forms of migraine (Nyholt et al., Reference Nyholt, LaForge, Kallela, Alakurtti, Anttila, Farkkila and Palotie2008). Our research also showed that despite the female:male prevalence ratio of >2:1, female and male migraineurs are not genetically distinct (Mulder et al., Reference Mulder, Van Baal, Gaist, Kallela, Kaprio, Svensson and Palotie2003; Nyholt et al., Reference Nyholt, Gillespie, Heath, Merikangas, Duffy and Martin2004, Reference Nyholt, Anttila, Winsvold, Kurth, Stefansson and Palotie2015). These advances were crucial to the design and execution of subsequent well-powered genetic studies of migraine — all led by the IHGC.
In 2016, we published the largest ever genetic study of migraine (involving 59,674 migraine cases and 316,078 controls) and identified 44 (34 new) risk variants for migraine (Gormley et al., Reference Gormley, Anttila, Winsvold, Palta, Esko, Pers and Palotie2016). Most prominently, this research provided valuable insight into migraine pathophysiology, by indicating vascular dysfunction to be a primary mechanism underlying migraine. This is important because there is a long-running debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. This paper’s Altmetric attention score is in the top 0.02% of all research outputs ever tracked. Moreover, the results from this study allow polygenic risk score (PRS) analyses in migraine risk prediction to identify and quantify comorbidities, endophenotypes and drug responses and paves the way to develop relevant vascular cellular models of migraine that are required to understand the molecular mechanisms of migraine and develop new drugs. Indeed, our migraine PRS was able to identify subgroups of patients likely to respond to triptans (an acute migraine drug), providing the first step toward precision medicine in migraine (Kogelman et al., Reference Kogelman, Esserlind, Christensen, Awasthi, Ripke and Ingason2019).
The above highlights are but a few of the many that I have been fortunate to share with Nick over the past 20 years, and I hope to share many more. As we celebrate Nick’s 70th birthday (besides from mentally noting his fitting Platinum Jubilee themed hair color), I fondly reflect on the countless discussions, opportunities and accomplishments we have shared and I marvel at the amazing legacy he continues to build for current and future generations. Cheers Nick, you are truly a unique and special individual.
